Journal of Clinical Outcomes Management

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

Health care providers are missing opportunities to give medical treatment to high-risk individuals hospitalized for alcohol use disorder (AUD), a national analysis of Medicare beneficiaries reported.

Increasing such patients’ access to psychiatric care and addiction medicine, as well as encouraging medication prescribing by generalists and nonaddiction specialists, are remedial strategies recommended by lead author Eden Y. Bernstein, MD, of the division of general internal medicine at Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues.

“Hospitalizations for alcohol use disorder are common,” Dr. Bernstein said in an interview. “Our work shows they represent an underutilized opportunity to engage patients with appropriate treatment, including initiation of medications for alcohol use disorder.”

There is a pressing need for such treatment strategies since 29 million U.S. adults have AUD, and alcohol contributes to more than 140,000 deaths annually, the authors noted.

Rarely initiated either at hospital discharge or during follow-up care, medical therapy for AUD was more likely to be provided to younger patients and those involved with psychiatric care or addiction medicine, Dr. Bernstein’s group reported in Annals of Internal Medicine.Hospital admissions, they argued, give patients more access to clinicians and social workers and the vulnerability experienced during hospitalization may motivate behavioral change.


 

National study

The cohort included 28,601 AUD hospitalizations for 20,401 unique Medicare patients from 2015 to 2017. About 30% of admissions were for women and about 72% for non-Hispanic Blacks. Discharge initiation of medication for AUD was defined as a pharmacy claim for naltrexone, acamprosate, or disulfiram from the day before discharge to 2 days after.

Overall, just 206 patients (0.7%) initiated medication for AUD within 2 days of discharge and 364 (1.3%) started it within 30 days. Among those discharged with a primary diagnosis of AUD, only 70 (2.3%) started medical therapy within 2 days.

The most predictive demographic factor for discharge medication for AUD was younger age: 18-39 years versus 75 years and older (adjusted odds ratio, 3.87; 95% confidence interval, 1.34-11.16).

Initiation of medication for AUD should involve a long-term treatment plan, according to Dr. Bernstein’s group, and if that is not feasible during hospitalization, patients should be referred for outpatient treatment.

An accompanying editorial agrees that the results offer strong evidence of a missed opportunity to address AUD at a potential flexion point. “Hospitalization is a critical touch point for identifying and treating AUD,” wrote Michael F. Mayo-Smith, MD, MPH, of White River Junction (Vt.) VA Medical Center, and Geisel School of Medicine at Dartmouth, Hanover, N.H., and David Lawrence, MD, of the VA Greater Los Angeles Healthcare System and the University of California, Los Angeles.

An intentional discharge protocol can be effective, they noted, as evidenced by a 2014 report in which this approach increased medication-assisted treatment from 0% to 64% in tandem with a decrease in all-cause, 30-day readmission rates.

“There is also growing interest in inpatient addiction consultation services, which have shown [medication] for AUD treatment initiation rates of up to 70% as well as improved engagement in posthospital treatment,” Dr. Mayo-Smith and Dr. Lawrence wrote.

Minority populations need particular attention, they added. “Unfortunately, the availability of evidence-based treatments for AUD does not by itself lead to improved care. We need strategies for widespread adoption so that patients can realize the benefits of these treatments.”

Dr. Bernstein reported funding support from a National Research Service Award and the Massachusetts General Hospital division of general internal medicine; he disclosed fees from Alosa Health. One coauthor was supported by the Agency for Healthcare Research and Quality. Another was supported by the National Institute on Aging and reported relationships with the American College of Cardiology, Boston OIAC Pepper Center, American Heart Association, and US Deprescribing Research Network. Dr. Mayo-Smith disclosed no competing interests. Dr. Lawrence reported fees related to presentations at DDW 2023 and the California Society of Addiction Medicine 2022.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

New data suggest a significantly stronger link in women compared with men between atrial fibrillation (AF) and mild cognitive impairment (MCI) and dementia.

“Our findings imply that women with AF may be at higher risk for MCI and dementia with potentially more rapid disease progression from normal cognition to MCI or dementia than women without AF or men with and without AF,” wrote authors of a new study led by Kathryn A. Wood, PhD, RN, Neil Hodgson Woodruff School of Nursing at Emory University in Atlanta.

The findings were published online in Alzheimer’s & Dementia.

Researchers used the National Alzheimer’s Coordinating Center data with 43,630 patients and analyzed sex differences between men and women with AF and their performance on neuropsychological tests and cognitive disease progression.

Higher odds of dementia, MCI in women

According to the paper, AF is associated with higher odds of dementia (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.22-7.37) in women and MCI in women (OR, 3.43; 95% CI, 1.55-7.55) compared with men.

Women with AF and normal cognition at baseline had a higher risk of disease progression (hazard ratio [HR], 1.26; 95% CI, 1.06-1.50) from normal to MCI and from MCI to vascular dementia (HR, 3.27; 95% CI, 1.89-5.65) than that of men with AF or men and women without AF. 

AF is a major public health problem linked with stroke and heart failure, and is an independent risk factor of increased mortality. It is associated with higher risk of cognitive impairment and dementia independent of stroke history.
 

Cognitive screening for AF patients

The authors wrote that cognitive screening, especially in women, should be part of yearly cardiology visits for patients with AF to help identify early those at highest risk for cognitive disease.

T. Jared Bunch, MD, professor of medicine in the division of cardiovascular medicine at University of Utah in Salt Lake City, said in an interview, “We have learned that how we treat atrial fibrillation can influence risk.”

First, he said, outcomes, including brain health, are better when rhythm control approaches are used within the first year of diagnosis. 

“Restoring a normal heart rhythm improves brain perfusion and cognitive function. Next, aggressive rhythm control – such as catheter ablation – is associated with much lower long-term risks of dementia in the [patients].  Finally, early and effective use of anticoagulation in patients with atrial fibrillation lowers risk of stroke, dementia, and cognitive decline.”
 

Several factors unknown

Dr. Bunch said there are some unknowns in the study, such as how long patients were in atrial fibrillation. 

He said one way to address the inequities is to refer women earlier as women are often referred later in disease to specialty care, which can have consequences.

He said it is not known how many people underwent early and effective rhythm control. 

“Women also are less likely to receive catheter ablation, a cardioversion, or be placed on antiarrhythmic drugs,” said Dr. Bunch, who was not part of the study. “These also represent potential opportunities to improve outcomes by treating the rhythm in a similar and aggressive manner in both men and women.”

Also unknown is how many people were on effective oral anticoagulation, Dr. Bunch noted.

The study importantly highlights a significant problem surrounding the care of women with AF, he said, but there are strategies to improve outcomes.

In addition to earlier screening and referral for women, providers should recognize that men and women may present differently with different AF symptoms. He added that physicians should offer catheter ablation, the most effective treatment, equally to men and women who are candidates.

In all people, he said, it’s important “to start anticoagulation very early in the disease to lower the risk of micro- and macrothrombotic events that lead to poor brain health and function.”

The study authors and Dr. Bunch declared no relevant financial relationships.

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

The Food and Drug Administration has approved the oral poly (ADP-ribose) polymerase inhibitor talazoparib (Talzenna, Pfizer) plus enzalutamide (Xtandi) to treat homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer.

Talazoparib is already approved for adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The new approval, granted following priority review, is based on findings from the randomized, placebo-controlled, phase 3 TALAPRO-2 trial, published in The Lancet.

The 399 patients in the study were randomly assigned in a 1:1 ratio to receive either enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Median radiographic progression-free survival (PFS) was not reached in the treatment group; it was 13.8 months in the placebo group (hazard ratio, 0.45). In an exploratory analysis by BRCA mutation status, patients with BRCA-mutated disease who received talazoparib exhibited an even stronger median radiographic PFS (HR, 0.20; not reached vs. 11 months) in comparison with those without BRCA-mutated disease (HR, 0.72; 24.7 vs. 16.7 months).

Serious adverse reactions occurred in 30% of patients who received talazoparib plus enzalutamide. The most common serious adverse reactions, reported in more than 2% of patients, included anemia (9%) and fracture (3%). Discontinuation of talazoparib occurred in 10% of patients, according to a Pfizer statement.

Pfizer also noted that a marketing authorization application for the drug combination has been accepted for review by the European Medicines Agency.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy,” lead investigator Neeraj Agarwal, MD, of the Huntsman Cancer Institute, University of Utah, Salt Lake City, said in a statement. Patients with metastatic castration-resistant prostate cancer harboring HRR genetic alterations have even worse outcomes, and thus the FDA’s approval of the talazoparib and enzalutamide combination “represents a treatment option deserving of excitement and attention.”

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

The Food and Drug Administration has approved the oral poly (ADP-ribose) polymerase inhibitor talazoparib (Talzenna, Pfizer) plus enzalutamide (Xtandi) to treat homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer.

Talazoparib is already approved for adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The new approval, granted following priority review, is based on findings from the randomized, placebo-controlled, phase 3 TALAPRO-2 trial, published in The Lancet.

The 399 patients in the study were randomly assigned in a 1:1 ratio to receive either enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Median radiographic progression-free survival (PFS) was not reached in the treatment group; it was 13.8 months in the placebo group (hazard ratio, 0.45). In an exploratory analysis by BRCA mutation status, patients with BRCA-mutated disease who received talazoparib exhibited an even stronger median radiographic PFS (HR, 0.20; not reached vs. 11 months) in comparison with those without BRCA-mutated disease (HR, 0.72; 24.7 vs. 16.7 months).

Serious adverse reactions occurred in 30% of patients who received talazoparib plus enzalutamide. The most common serious adverse reactions, reported in more than 2% of patients, included anemia (9%) and fracture (3%). Discontinuation of talazoparib occurred in 10% of patients, according to a Pfizer statement.

Pfizer also noted that a marketing authorization application for the drug combination has been accepted for review by the European Medicines Agency.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy,” lead investigator Neeraj Agarwal, MD, of the Huntsman Cancer Institute, University of Utah, Salt Lake City, said in a statement. Patients with metastatic castration-resistant prostate cancer harboring HRR genetic alterations have even worse outcomes, and thus the FDA’s approval of the talazoparib and enzalutamide combination “represents a treatment option deserving of excitement and attention.”

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

The Food and Drug Administration has approved the oral poly (ADP-ribose) polymerase inhibitor talazoparib (Talzenna, Pfizer) plus enzalutamide (Xtandi) to treat homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer.

Talazoparib is already approved for adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. The new approval, granted following priority review, is based on findings from the randomized, placebo-controlled, phase 3 TALAPRO-2 trial, published in The Lancet.

The 399 patients in the study were randomly assigned in a 1:1 ratio to receive either enzalutamide 160 mg daily plus either talazoparib 0.5 mg or placebo daily. Median radiographic progression-free survival (PFS) was not reached in the treatment group; it was 13.8 months in the placebo group (hazard ratio, 0.45). In an exploratory analysis by BRCA mutation status, patients with BRCA-mutated disease who received talazoparib exhibited an even stronger median radiographic PFS (HR, 0.20; not reached vs. 11 months) in comparison with those without BRCA-mutated disease (HR, 0.72; 24.7 vs. 16.7 months).

Serious adverse reactions occurred in 30% of patients who received talazoparib plus enzalutamide. The most common serious adverse reactions, reported in more than 2% of patients, included anemia (9%) and fracture (3%). Discontinuation of talazoparib occurred in 10% of patients, according to a Pfizer statement.

Pfizer also noted that a marketing authorization application for the drug combination has been accepted for review by the European Medicines Agency.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy,” lead investigator Neeraj Agarwal, MD, of the Huntsman Cancer Institute, University of Utah, Salt Lake City, said in a statement. Patients with metastatic castration-resistant prostate cancer harboring HRR genetic alterations have even worse outcomes, and thus the FDA’s approval of the talazoparib and enzalutamide combination “represents a treatment option deserving of excitement and attention.”

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

AUSTIN, TEX – Migraine treatment and prevention is challenging in any population, but some present even more difficulties. Pregnant women and pediatric patients are two such groups where physicians and patients may be hesitant to use drugs.

Neuromodulation devices are proven alternatives to medical interventions, and the remote electrical neuromodulation device Nerivio (Theranica) was cleared by the Food and Drug Administration for acute treatment of migraine patients aged 12 and over in 2021. In March 2023, the agency expanded the clearance to include prevention of migration in adolescents aged 12 and over as well as adults.

Two studies presented at the annual meeting of the American Headache Society showed the safety of the remote electrical neuromodulation device in pregnant women and efficacy as a preventive measure in adolescents in a real-world setting. The latter study yielded similar findings to adults and was used by FDA in its decision to expand the device’s indication in adolescents in 2023, according to Teshamae Monteith, MD, who presented the study at a poster session.

The device, worn on the arm, allows the user to modulate the intensity of the stimulation so that it activates nociceptive pain receptors, but not in a painful way. “Each [patient] raises the intensity until it feels strong, yet comfortable, and when that happens, they activate the nociceptive receptors and the arm sends a signal all the way back up to the brainstem, where the pain control area is. Activating it causes the release of neurotransmitters that inhibit pain. That inhibition is a global pain inhibition mechanism, which causes inhibition of the migraine pain, and also the symptoms associated with migraine like photophobia and vomiting,” said Alit Stark-Inbar, PhD, who presented the study of treatment of pregnant women during a poster session.
 

Declining treatment days over time in adolescents

Dr. Monteith’s team studied high-frequency remote electrical neuromodulation device use in adolescents who had migraine on 10 days or more per month. They also required at least three treatment days in months 2 and 3 to control for the possibility that patients might stop using the device because they couldn’t afford it or for some reason other than efficacy or because their migraines went away.

The study included 83 adolescents aged 12-17 (mean, 15.9 years, 89% female). In the first month of use, the mean number of migraine treatment days was 12.6, which dropped to 9.0 in month 2 (P < .001), and 7.4 in month 3 (P < .001 from month 2). At 2 hours after treatment, 61.9% had pain relief, 24.5% had freedom from pain, 67.4% had functional disability relief, and 41.3% had functional disability freedom.

“It parallels the findings of the randomized, sham-controlled study in adults. The safety profile was excellent with just one person complaining of minor discomfort of the arm that resolved after treatment. The combination of the exceedingly safe profile and the likelihood of efficacy based on using monthly migraine treatment days as a proxy, the FDA decided to clear this for an adolescent indication,” said Dr. Monteith, associate professor of clinical neurology and chief of the headache division at the University of Miami.

The device design is convenient, according to Dr. Monteith. “The arm is just an easy place to stimulate. It’s a wearable device, and it’s 45 minutes [of treatment] and it’s app controlled. You know adolescents like their technology. They can track their symptoms here, and there’s some biobehavioral power to this because they can do biobehavioral exercises in addition to receiving the simulation,” she said.

The fact that the device is discrete is also an advantage for adolescents in school. “You have to go to the nurse to get your medication versus a device, you can just put it on, it’s easy, no one sees it, and no one’s making fun of you,” said Dr. Monteith.
 

Advantages for adolescents

The device offers a useful alternative to medication, according to Alan M. Rapoport, MD, who was asked for comment on the adolescent study. “I’d rather not give medication and certainly not preventive medication to an adolescent,” he said. He noted that over-the-counter acute care migraine medications such as aspirin or acetaminophen and combination medications with caffeine, as well as prescription medications such as triptans, “all have possible side effects, and when used to an increased extent can even cause medication overuse headache, increasing the severity and frequency of headache and migraine days per month,” Dr. Rapoport said. Using an effective device with almost no side effects is preferable to any of these acute care medications, especially if there are several headaches a month,” he said. Some newer medications that block calcitonin gene-related peptide might be quite effective when they are approved for adolescents, and should have few adverse events, he added.

In the past, Dr. Rapoport has favored biofeedback training for acute and especially preventive treatment of migraine in adolescents. “[Remote electrical neuromodulation] seems to do just as well, children enjoy it, and it’s easier for a patient to do at home,” said Dr. Rapoport.

Biofeedback training is usually taught to patients by a PhD psychologist. Once the patients have been on the biofeedback equipment and learn the techniques, they can practice on their own at home without equipment. “This new device treatment using Nerivio for acute care and prevention of migraine in adults and children 12 and older, where they can easily apply the device in almost any situation, whether they are at home or possibly even in school or out and about, looks very promising,” said Dr. Rapoport. It is quite effective and has almost no adverse events, which is what you really want, especially for adolescents,” he said.

Also asked to comment on the study of remote electrical neuromodulation use in adolescents, Abraham Avi Ashkenazi, MD, director of the Headache Clinic at Shaare Zedek Medical Center in Jerusalem, who attended the session, was enthusiastic, and said he has begun using it in his own practice. “It shows that remote electrical neuromodulation can not only be effective for the acute migraine attack, but also has a potential preventive effect on future migraine attacks. [This] actually makes sense, because we know that the more migraine attacks a person has, the more likely they are to progress to a more chronic form of the disease,” he said in an interview.

Asked what distinguishes REN from other neuromodulation therapies such as vagus nerve stimulation or transcranial magnetic stimulation (TMS), Dr. Ashkenazi said: “It’s just a different way of modulating the brain system via a different mechanism. In both ways, though, the advantage is that there are literally no adverse effects, as opposed to drug treatment.”
 

An alternative during pregnancy

Adolescents aren’t the only population where there is reluctance to use medication. Physicians have been prescribing the device for pregnant women, who are reluctant to take medication due to concerns effects on the fetus. However, pregnant women were not included in the pivotal studies. “They expect it to be safe. This study was done in order to validate that assumption. We reached out to women who either used the device during pregnancy or women from the same database who started it using afterwards, but did not use it during the pregnancy,” said Dr. Stark-Inbar, vice president of medical information at Theranica.

The study included 140 women, 59 in the remote electrical neuromodulation device group and 81 controls. The primary endpoint was gestational age, which was 38 weeks and 5 days in the remote electrical neuromodulation device group and 39 weeks among controls (P = .150). There were no significant between-group differences with respect to newborn birth weight, miscarriage rate, preterm birth rate, birth defect rate, developmental milestone rate, or emergency department visit rate.

Dr. Monteith and Dr. Ashkenazi have no relevant financial disclosures. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. Dr. Rapoport is the editor-in-chief of Neurology Reviews and on the editorial board of CNS Drugs.

AUSTIN, TEX – Migraine treatment and prevention is challenging in any population, but some present even more difficulties. Pregnant women and pediatric patients are two such groups where physicians and patients may be hesitant to use drugs.

Neuromodulation devices are proven alternatives to medical interventions, and the remote electrical neuromodulation device Nerivio (Theranica) was cleared by the Food and Drug Administration for acute treatment of migraine patients aged 12 and over in 2021. In March 2023, the agency expanded the clearance to include prevention of migration in adolescents aged 12 and over as well as adults.

Two studies presented at the annual meeting of the American Headache Society showed the safety of the remote electrical neuromodulation device in pregnant women and efficacy as a preventive measure in adolescents in a real-world setting. The latter study yielded similar findings to adults and was used by FDA in its decision to expand the device’s indication in adolescents in 2023, according to Teshamae Monteith, MD, who presented the study at a poster session.

The device, worn on the arm, allows the user to modulate the intensity of the stimulation so that it activates nociceptive pain receptors, but not in a painful way. “Each [patient] raises the intensity until it feels strong, yet comfortable, and when that happens, they activate the nociceptive receptors and the arm sends a signal all the way back up to the brainstem, where the pain control area is. Activating it causes the release of neurotransmitters that inhibit pain. That inhibition is a global pain inhibition mechanism, which causes inhibition of the migraine pain, and also the symptoms associated with migraine like photophobia and vomiting,” said Alit Stark-Inbar, PhD, who presented the study of treatment of pregnant women during a poster session.
 

Declining treatment days over time in adolescents

Dr. Monteith’s team studied high-frequency remote electrical neuromodulation device use in adolescents who had migraine on 10 days or more per month. They also required at least three treatment days in months 2 and 3 to control for the possibility that patients might stop using the device because they couldn’t afford it or for some reason other than efficacy or because their migraines went away.

The study included 83 adolescents aged 12-17 (mean, 15.9 years, 89% female). In the first month of use, the mean number of migraine treatment days was 12.6, which dropped to 9.0 in month 2 (P < .001), and 7.4 in month 3 (P < .001 from month 2). At 2 hours after treatment, 61.9% had pain relief, 24.5% had freedom from pain, 67.4% had functional disability relief, and 41.3% had functional disability freedom.

“It parallels the findings of the randomized, sham-controlled study in adults. The safety profile was excellent with just one person complaining of minor discomfort of the arm that resolved after treatment. The combination of the exceedingly safe profile and the likelihood of efficacy based on using monthly migraine treatment days as a proxy, the FDA decided to clear this for an adolescent indication,” said Dr. Monteith, associate professor of clinical neurology and chief of the headache division at the University of Miami.

The device design is convenient, according to Dr. Monteith. “The arm is just an easy place to stimulate. It’s a wearable device, and it’s 45 minutes [of treatment] and it’s app controlled. You know adolescents like their technology. They can track their symptoms here, and there’s some biobehavioral power to this because they can do biobehavioral exercises in addition to receiving the simulation,” she said.

The fact that the device is discrete is also an advantage for adolescents in school. “You have to go to the nurse to get your medication versus a device, you can just put it on, it’s easy, no one sees it, and no one’s making fun of you,” said Dr. Monteith.
 

Advantages for adolescents

The device offers a useful alternative to medication, according to Alan M. Rapoport, MD, who was asked for comment on the adolescent study. “I’d rather not give medication and certainly not preventive medication to an adolescent,” he said. He noted that over-the-counter acute care migraine medications such as aspirin or acetaminophen and combination medications with caffeine, as well as prescription medications such as triptans, “all have possible side effects, and when used to an increased extent can even cause medication overuse headache, increasing the severity and frequency of headache and migraine days per month,” Dr. Rapoport said. Using an effective device with almost no side effects is preferable to any of these acute care medications, especially if there are several headaches a month,” he said. Some newer medications that block calcitonin gene-related peptide might be quite effective when they are approved for adolescents, and should have few adverse events, he added.

In the past, Dr. Rapoport has favored biofeedback training for acute and especially preventive treatment of migraine in adolescents. “[Remote electrical neuromodulation] seems to do just as well, children enjoy it, and it’s easier for a patient to do at home,” said Dr. Rapoport.

Biofeedback training is usually taught to patients by a PhD psychologist. Once the patients have been on the biofeedback equipment and learn the techniques, they can practice on their own at home without equipment. “This new device treatment using Nerivio for acute care and prevention of migraine in adults and children 12 and older, where they can easily apply the device in almost any situation, whether they are at home or possibly even in school or out and about, looks very promising,” said Dr. Rapoport. It is quite effective and has almost no adverse events, which is what you really want, especially for adolescents,” he said.

Also asked to comment on the study of remote electrical neuromodulation use in adolescents, Abraham Avi Ashkenazi, MD, director of the Headache Clinic at Shaare Zedek Medical Center in Jerusalem, who attended the session, was enthusiastic, and said he has begun using it in his own practice. “It shows that remote electrical neuromodulation can not only be effective for the acute migraine attack, but also has a potential preventive effect on future migraine attacks. [This] actually makes sense, because we know that the more migraine attacks a person has, the more likely they are to progress to a more chronic form of the disease,” he said in an interview.

Asked what distinguishes REN from other neuromodulation therapies such as vagus nerve stimulation or transcranial magnetic stimulation (TMS), Dr. Ashkenazi said: “It’s just a different way of modulating the brain system via a different mechanism. In both ways, though, the advantage is that there are literally no adverse effects, as opposed to drug treatment.”
 

An alternative during pregnancy

Adolescents aren’t the only population where there is reluctance to use medication. Physicians have been prescribing the device for pregnant women, who are reluctant to take medication due to concerns effects on the fetus. However, pregnant women were not included in the pivotal studies. “They expect it to be safe. This study was done in order to validate that assumption. We reached out to women who either used the device during pregnancy or women from the same database who started it using afterwards, but did not use it during the pregnancy,” said Dr. Stark-Inbar, vice president of medical information at Theranica.

The study included 140 women, 59 in the remote electrical neuromodulation device group and 81 controls. The primary endpoint was gestational age, which was 38 weeks and 5 days in the remote electrical neuromodulation device group and 39 weeks among controls (P = .150). There were no significant between-group differences with respect to newborn birth weight, miscarriage rate, preterm birth rate, birth defect rate, developmental milestone rate, or emergency department visit rate.

Dr. Monteith and Dr. Ashkenazi have no relevant financial disclosures. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. Dr. Rapoport is the editor-in-chief of Neurology Reviews and on the editorial board of CNS Drugs.

AUSTIN, TEX – Migraine treatment and prevention is challenging in any population, but some present even more difficulties. Pregnant women and pediatric patients are two such groups where physicians and patients may be hesitant to use drugs.

Neuromodulation devices are proven alternatives to medical interventions, and the remote electrical neuromodulation device Nerivio (Theranica) was cleared by the Food and Drug Administration for acute treatment of migraine patients aged 12 and over in 2021. In March 2023, the agency expanded the clearance to include prevention of migration in adolescents aged 12 and over as well as adults.

Two studies presented at the annual meeting of the American Headache Society showed the safety of the remote electrical neuromodulation device in pregnant women and efficacy as a preventive measure in adolescents in a real-world setting. The latter study yielded similar findings to adults and was used by FDA in its decision to expand the device’s indication in adolescents in 2023, according to Teshamae Monteith, MD, who presented the study at a poster session.

The device, worn on the arm, allows the user to modulate the intensity of the stimulation so that it activates nociceptive pain receptors, but not in a painful way. “Each [patient] raises the intensity until it feels strong, yet comfortable, and when that happens, they activate the nociceptive receptors and the arm sends a signal all the way back up to the brainstem, where the pain control area is. Activating it causes the release of neurotransmitters that inhibit pain. That inhibition is a global pain inhibition mechanism, which causes inhibition of the migraine pain, and also the symptoms associated with migraine like photophobia and vomiting,” said Alit Stark-Inbar, PhD, who presented the study of treatment of pregnant women during a poster session.
 

Declining treatment days over time in adolescents

Dr. Monteith’s team studied high-frequency remote electrical neuromodulation device use in adolescents who had migraine on 10 days or more per month. They also required at least three treatment days in months 2 and 3 to control for the possibility that patients might stop using the device because they couldn’t afford it or for some reason other than efficacy or because their migraines went away.

The study included 83 adolescents aged 12-17 (mean, 15.9 years, 89% female). In the first month of use, the mean number of migraine treatment days was 12.6, which dropped to 9.0 in month 2 (P < .001), and 7.4 in month 3 (P < .001 from month 2). At 2 hours after treatment, 61.9% had pain relief, 24.5% had freedom from pain, 67.4% had functional disability relief, and 41.3% had functional disability freedom.

“It parallels the findings of the randomized, sham-controlled study in adults. The safety profile was excellent with just one person complaining of minor discomfort of the arm that resolved after treatment. The combination of the exceedingly safe profile and the likelihood of efficacy based on using monthly migraine treatment days as a proxy, the FDA decided to clear this for an adolescent indication,” said Dr. Monteith, associate professor of clinical neurology and chief of the headache division at the University of Miami.

The device design is convenient, according to Dr. Monteith. “The arm is just an easy place to stimulate. It’s a wearable device, and it’s 45 minutes [of treatment] and it’s app controlled. You know adolescents like their technology. They can track their symptoms here, and there’s some biobehavioral power to this because they can do biobehavioral exercises in addition to receiving the simulation,” she said.

The fact that the device is discrete is also an advantage for adolescents in school. “You have to go to the nurse to get your medication versus a device, you can just put it on, it’s easy, no one sees it, and no one’s making fun of you,” said Dr. Monteith.
 

Advantages for adolescents

The device offers a useful alternative to medication, according to Alan M. Rapoport, MD, who was asked for comment on the adolescent study. “I’d rather not give medication and certainly not preventive medication to an adolescent,” he said. He noted that over-the-counter acute care migraine medications such as aspirin or acetaminophen and combination medications with caffeine, as well as prescription medications such as triptans, “all have possible side effects, and when used to an increased extent can even cause medication overuse headache, increasing the severity and frequency of headache and migraine days per month,” Dr. Rapoport said. Using an effective device with almost no side effects is preferable to any of these acute care medications, especially if there are several headaches a month,” he said. Some newer medications that block calcitonin gene-related peptide might be quite effective when they are approved for adolescents, and should have few adverse events, he added.

In the past, Dr. Rapoport has favored biofeedback training for acute and especially preventive treatment of migraine in adolescents. “[Remote electrical neuromodulation] seems to do just as well, children enjoy it, and it’s easier for a patient to do at home,” said Dr. Rapoport.

Biofeedback training is usually taught to patients by a PhD psychologist. Once the patients have been on the biofeedback equipment and learn the techniques, they can practice on their own at home without equipment. “This new device treatment using Nerivio for acute care and prevention of migraine in adults and children 12 and older, where they can easily apply the device in almost any situation, whether they are at home or possibly even in school or out and about, looks very promising,” said Dr. Rapoport. It is quite effective and has almost no adverse events, which is what you really want, especially for adolescents,” he said.

Also asked to comment on the study of remote electrical neuromodulation use in adolescents, Abraham Avi Ashkenazi, MD, director of the Headache Clinic at Shaare Zedek Medical Center in Jerusalem, who attended the session, was enthusiastic, and said he has begun using it in his own practice. “It shows that remote electrical neuromodulation can not only be effective for the acute migraine attack, but also has a potential preventive effect on future migraine attacks. [This] actually makes sense, because we know that the more migraine attacks a person has, the more likely they are to progress to a more chronic form of the disease,” he said in an interview.

Asked what distinguishes REN from other neuromodulation therapies such as vagus nerve stimulation or transcranial magnetic stimulation (TMS), Dr. Ashkenazi said: “It’s just a different way of modulating the brain system via a different mechanism. In both ways, though, the advantage is that there are literally no adverse effects, as opposed to drug treatment.”
 

An alternative during pregnancy

Adolescents aren’t the only population where there is reluctance to use medication. Physicians have been prescribing the device for pregnant women, who are reluctant to take medication due to concerns effects on the fetus. However, pregnant women were not included in the pivotal studies. “They expect it to be safe. This study was done in order to validate that assumption. We reached out to women who either used the device during pregnancy or women from the same database who started it using afterwards, but did not use it during the pregnancy,” said Dr. Stark-Inbar, vice president of medical information at Theranica.

The study included 140 women, 59 in the remote electrical neuromodulation device group and 81 controls. The primary endpoint was gestational age, which was 38 weeks and 5 days in the remote electrical neuromodulation device group and 39 weeks among controls (P = .150). There were no significant between-group differences with respect to newborn birth weight, miscarriage rate, preterm birth rate, birth defect rate, developmental milestone rate, or emergency department visit rate.

Dr. Monteith and Dr. Ashkenazi have no relevant financial disclosures. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureau of AbbVie, Dr. Reddy’s, Impel, Pfizer and Teva Pharmaceutical Industries. Dr. Rapoport is the editor-in-chief of Neurology Reviews and on the editorial board of CNS Drugs.

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

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

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

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

The recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco; Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD) represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

The Food and Drug Administration granted colchicine a very broad label: to reduce the risk for cardiovascular events in adult patients with established ASCVD or with multiple risk factors for cardiovascular disease. But how will the drug be used in clinical practice?

“The idea of inflammation as a driver of atherosclerosis and cardiovascular risk has been around for decades, and it is very well known that atherosclerosis is an inflammatory process. However, treating inflammation is new as we haven’t had a specific agent targeting inflammation before, noted Michael Joseph Blaha, MD, director of clinical research, Ciccarone Center for the Prevention of Cardiovascular Disease at Johns Hopkins Hospital, Baltimore.

Dr. Blaha, who has been an unpaid scientific adviser to Agepha, added that the approval of low-dose colchicine “will open the door toward having a routine conversation about residual inflammatory risk in our patients; and we need to work out exactly how we do that.”

Dr. Blaha is not surprised by the FDA-approved indication for colchicine, pointing out that the main large-scale trial supporting its use in ASCVD, the LoDoCo-2 trial, included a similar broad population.

“I think the approval was appropriate as the indication should always follow the data. But I think how the drug will actually be used will depend on the context for different individual patients,” he said.

“The paradigm coming forward is the idea of residual risk that patients have after they been treated with the standard of care – which in most cases is a statin and blood pressure control – and what is driving that residual risk,” he noted. “If we think patients are still at high risk of recurrent cardiovascular events, we have to think what we will do next. This is where this drug will come in.”

Dr. Blaha pointed out that there are now multiple options for reducing residual risk; he believes that it will depend on the profile of the patient as to which of those options is chosen first.

“If after high-dose statin treatment they still have raised LDL, then we can add another LDL lowering drug; or it might be diabetes and obesity that we want to address first; or elevated triglycerides. But now, we can also consider residual inflammatory risk if we think the patient has residual plaque inflammation,” he said. “So, colchicine will be one of several choices beyond a statin that we can think about as the next step for treating residual risk.”
 

Is CRP measurement necessary?

Though elevated levels of high-sensitivity C-reactive protein (hsCRP) is a marker of inflammation in ASCVD, the two main trials of colchicine in ASCVD, both of which showed large benefits of the drug, did not measure hsCRP, leading to questions as to whether measurement of this biomarker is necessary to select patients for colchicine treatment.

“Some clinicians will favor testing hsCRP and treating those with levels above 2 mg/L. I think that’s very reasonable,” Dr. Blaha said. “However, because hsCRP was not measured in the trials, I don’t think testing for this biomarker is mandatory to establish that there is inflammation,” he added.

“The label does not stipulate that CRP has to be measured. It is giving physicians latitude; they can measure CRP, or they don’t have to.”

Dr. Blaha added that clinicians need to think about what is driving residual risk in each individual patient: “If you think their other risk factors are well controlled but they are still having recurrent events, then we can consider colchicine as a way of reducing their residual risk which is likely being caused by inflammation.

“We are at a great place in cardiovascular medicine as we have several different options to use after a statin, and now we have this new therapy targeted at inflammation as well. While we can use all these options together, I think most clinicians will want to prioritize therapies by using the ones that they believe will reduce the residual risk the most in each individual patient,” Dr. Blaha explained.
 

‘An entire other axis driving atherosclerosis’

Paul Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston, is one of the major players in the cardiovascular inflammation field and has helped develop hsCRP testing. He has similar views.

“This FDA approval is extremely important, as it will draw attention to the role of inflammation in atherosclerosis and the need to treat it,” he said.

“Physicians need to be aware that, yes, we need to lower cholesterol aggressively, but they also need to know that there is an entire other axis driving atherosclerosis – and that is inflammation. And until now, we haven’t had an FDA-approved drug to treat inflammation.”

Dr. Ridker stressed that he doesn’t want to undermine lowering lipids: “Therapies aimed at inflammation are not in competition with those aimed at lipid lowering. We know lipid lowering works. But now we have another approach as well. The challenge here is educating physicians on this new approach.”

Dr. Ridker said he already uses low-dose colchicine for patients whom he refers to as “frequent flyers”; those who keep coming back despite aggressive lipid lowering. “They have multiple angioplasties, bypass surgery, etc.”

Like Dr. Blaha, Dr. Ridker thinks that doctors should start using this drug in high-risk patients who are already on a statin and who have residual inflammatory risk: “[The] patient whose underlying biologic problem is inflammation [is whom] we really want to treat with this drug. That is where it is most likely to be highly effective and where the comfort level will be the greatest.”

He said that measurement of hsCRP is an appropriate way to select these patients.

“I think this is a great impetus to start having much wider CRP measurement so we can actually target this anti-inflammatory drug to the patients with residual inflammatory risk – those with hsCRP level above 2 mg/L,” he said, estimating that this could apply to around 30%-40% of patients with ASCVD who are already taking a statin.
 

A second pillar of ASCVD treatment?

A somewhat different view is held by Jean-Claude Tardif, MD, director of the Research Centre at the Montréal Heart Institute, Canada, who was the lead investigator of the other randomized controlled trial of colchicine in heart disease, the COLCOT trial.

He said that colchicine should become the “second pillar” of ASCVD treatment, along with statins, for almost all patients.

Tardif referred to the recent study (led by Dr. Ridker) in The Lancet, which showed that among patients who are already on a statin, those with high inflammation levels had the highest risk for future events.

“So, the next step after a statin has to be to consider inflammation reduction,” he said.

“Despite all the drugs we have, ASCVD remains the leading cause of death in the Western world. What drives these events is largely inflammation, so it makes sense to directly tackle reduction of inflammation in the vessel, with a drug like colchicine,” he noted.

“I would say all patients with coronary atherosclerosis are potential candidates for low-dose colchicine as long as they do not have severe kidney disease, which is a contraindication,” Dr. Tardif said.

“If you want to fine tune this a bit more, those that are at particular risk are those that have recurrent events, those with multiple risk factors, and those with a recent [myocardial infarction]. In these patients, it would make a lot of sense to add low-dose colchicine to high-dose statins,” he added.

Dr. Tardif said he is not going to use CRP measurements to select patients for colchicine treatment: “Although measuring CRP may make sense intuitively, both large, randomized trials of colchicine did not select patients based on raised CRP, and they showed a benefit across the board.

If I consider a patient with ASCVD to be at high risk of future events and they are already on a statin I’m going to consider colchicine in all these patients, as long as they don’t have severe kidney disease.”

Dr. Tardif said that ASCVD needs to follow the model of heart failure which has several pillars of treatment directed at different targets that are all used together.

“I think we should apply the same approach to patients with ASCVD,” he added. “Yes, we need to hit the cholesterol with a statin, but we can now also hit the inflammation with colchicine.”
 

Polypharmacy concerns

Steve Nissen, MD, professor of medicine at the Cleveland Clinic, who was not involved in the colchicine trials, is also enthusiastic about use of colchicine. But like Dr. Ridker and Dr. Blaha, he favors selecting patients who are likely to benefit the most.

“I have been an advocate of the inflammatory hypothesis for many years, and we have been on a quest for a pure anti-inflammatory therapy that we can add to the standard treatment of patients with coronary disease. And colchicine has the safety and efficacy to do this,” Dr. Nissen said.

“What colchicine offers here is an inexpensive drug with pretty good data on reduction in morbidity from coronary disease. It has a completely different mechanism, so its benefit is likely to be additive to statins. I think we could probably do a lot of good at very little expense by just using these two therapies,” he said.

“But at present my preference will be to use colchicine selectively in those with raised CRP. I think that’s logical. I’m just worried about polypharmacy. Some of my patients are already on five, six, or seven meds. I need to have a reason to add an additional drug, and I’m not sure if we really analyze this carefully that patients with a low CRP would derive the same benefit. They might do, but I doubt it,” he noted.

“There may be further research and analyses that help us understand the relationship between CRP and efficacy of colchicine, and that may help us figure this out,” he added.
 

Safety is reassuring

In terms of safety and tolerability of the 0.5-mg colchicine dose, the experts seem to think that this is very manageable.

“When used for gout or pericarditis, colchicine is generally given at a dose of 0.6 mg twice a day and this can cause a lot of gastrointestinal [GI] side effects,” Dr. Nissen said. “But the low dose approved for ASCVD – 0.5 mg once a day – appears to be much better tolerated. There are some GI side effects, but these are not intolerable, and they generally go away with time.”

Dr. Ridker added that in the randomized trials, the adverse effects were “quite minimal,” but, “that being said, this drug is not to be used in severe kidney or liver disease, and there are some drug interactions that we need to be aware of. But in general, side effects are rare with the low dose. There may be some GI effects but they are mainly mild and you can generally treat through them.”

Dr. Blaha agreed that this is not a drug for patients with advanced kidney disease, “and there are some drug interactions that we have to be mindful of, but the list is not so long. There is a signal of modest gastrointestinal and muscle side effects, but most patients will be able to take it without issues. Because it’s already used in gout, physicians are already quite comfortable with its use.”
 

Part of the backbone of CV treatment?

Concluding, Dr. Blaha said he believes that prescribing of colchicine will start with cardiologists who will use it in their highest-risk patients first.

“But as we become comfortable with it, I think we will start using it in a broader range of patients and eventually primary care doctors will start prescribing it – much like what has happened with the statins,” he suggested.

“Where it sits along with statins in the future will be very interesting to see, but I think some people can envision it being up there with statins as part of the backbone of cardiovascular treatment in future.”

Dr. Tardif holds patents on methods for using low-dose colchicine after myocardial infarction, licensed to Montreal Heart Institute. Dr. Ridker is a consultant to Agepha and has research grants from Novo Nordisk related to the development of alternative anti-inflammatory therapies for atherosclerotic disease. Dr. Blaha reports being an unpaid scientific adviser to Agepha Pharma.

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

Omitting race and ethnicity from colorectal cancer (CRC) recurrence risk prediction models could decrease their accuracy and fairness, particularly for minority groups, potentially leading to inappropriate care advice and contributing to existing health disparities, new research suggests.

“Our study has important implications for developing clinical algorithms that are both accurate and fair,” write first author Sara Khor, MASc, with University of Washington, Seattle, and colleagues.

“Many groups have called for the removal of race in clinical algorithms,” Dr. Khor said in an interview. “We wanted to better understand, using CRC recurrence as a case study, what some of the implications might be if we simply remove race as a predictor in a risk prediction algorithm.”

Their findings suggest that doing so could lead to higher racial bias in model accuracy and less accurate estimation of risk for racial and ethnic minority groups. This could lead to inadequate or inappropriate surveillance and follow-up care more often in patients of minoritized racial and ethnic groups.

The study was published online in JAMA Network Open.
 

Lack of data and consensus

There is currently a lack of consensus on whether and how race and ethnicity should be included in clinical risk prediction models used to guide health care decisions, the authors note.

The inclusion of race and ethnicity in clinical risk prediction algorithms has come under increased scrutiny, because of concerns over the potential for racial profiling and biased treatment. On the other hand, some argue that excluding race and ethnicity could harm all groups by reducing predictive accuracy and would especially disadvantage minority groups.

It remains unclear whether simply omitting race and ethnicity from algorithms will ultimately improve care decisions for patients of minoritized racial and ethnic groups.

Dr. Khor and colleagues investigated the performance of four risk prediction models for CRC recurrence using data from 4,230 patients with CRC (53% non-Hispanic white; 22% Hispanic; 13% Black or African American; and 12% Asian, Hawaiian, or Pacific Islander).

The four models were:

• A race-neutral model that explicitly excluded race and ethnicity as a predictor.
• A race-sensitive model that included race and ethnicity.
• A model with two-way interactions between clinical predictors and race and ethnicity.
• Separate models stratified by race and ethnicity.

They found that the race-neutral model had poorer performance (worse calibration, negative predictive value, and false-negative rates) among racial and ethnic minority subgroups, compared with the non-Hispanic subgroup. The false-negative rate for Hispanic patients was 12% vs. 3% for non-Hispanic white patients.

Conversely, including race and ethnicity as a predictor of postoperative cancer recurrence improved the model’s accuracy and increased “algorithmic fairness” in terms of calibration slope, discriminative ability, positive predictive value, and false-negative rates. The false-negative rate for Hispanic patients was 9% and 8% for non-Hispanic white patients.

The inclusion of race interaction terms or using race-stratified models did not improve model fairness, likely due to small sample sizes in subgroups, the authors add.
 

‘No one-size-fits-all answer’

“There is no one-size-fits-all answer to whether race/ethnicity should be included, because the health disparity consequences that can result from each clinical decision are different,” Dr. Khor told this news organization.

“The downstream harms and benefits of including or excluding race will need to be carefully considered in each case,” Dr. Khor said.

“When developing a clinical risk prediction algorithm, one should consider the potential racial/ethnic biases present in clinical practice, which translate to bias in the data,” Dr. Khor added. “Care must be taken to think through the implications of such biases during the algorithm development and evaluation process in order to avoid further propagating those biases.”

The coauthors of a linked commentary say this study “highlights current challenges in measuring and addressing algorithmic bias, with implications for both patient care and health policy decision-making.”

Ankur Pandya, PhD, with Harvard School of Public Health, Boston, and Jinyi Zhu, PhD, with Vanderbilt University, Nashville, Tenn., agree that there is no “one-size-fits-all solution” – such as always excluding race and ethnicity from risk models – to confronting algorithmic bias.

“When possible, approaches for identifying and responding to algorithmic bias should focus on the decisions made by patients and policymakers as they relate to the ultimate outcomes of interest (such as length of life, quality of life, and costs) and the distribution of these outcomes across the subgroups that define important health disparities,” Dr. Pandya and Dr. Zhu suggest.

“What is most promising,” they write, is the high level of engagement from researchers, philosophers, policymakers, physicians and other healthcare professionals, caregivers, and patients to this cause in recent years, “suggesting that algorithmic bias will not be left unchecked as access to unprecedented amounts of data and methods continues to increase moving forward.”

This research was supported by a grant from the National Cancer Institute of the National Institutes of Health. The authors and editorial writers have disclosed no relevant financial relationships.

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

Omitting race and ethnicity from colorectal cancer (CRC) recurrence risk prediction models could decrease their accuracy and fairness, particularly for minority groups, potentially leading to inappropriate care advice and contributing to existing health disparities, new research suggests.

“Our study has important implications for developing clinical algorithms that are both accurate and fair,” write first author Sara Khor, MASc, with University of Washington, Seattle, and colleagues.

“Many groups have called for the removal of race in clinical algorithms,” Dr. Khor said in an interview. “We wanted to better understand, using CRC recurrence as a case study, what some of the implications might be if we simply remove race as a predictor in a risk prediction algorithm.”

Their findings suggest that doing so could lead to higher racial bias in model accuracy and less accurate estimation of risk for racial and ethnic minority groups. This could lead to inadequate or inappropriate surveillance and follow-up care more often in patients of minoritized racial and ethnic groups.

The study was published online in JAMA Network Open.
 

Lack of data and consensus

There is currently a lack of consensus on whether and how race and ethnicity should be included in clinical risk prediction models used to guide health care decisions, the authors note.

The inclusion of race and ethnicity in clinical risk prediction algorithms has come under increased scrutiny, because of concerns over the potential for racial profiling and biased treatment. On the other hand, some argue that excluding race and ethnicity could harm all groups by reducing predictive accuracy and would especially disadvantage minority groups.

It remains unclear whether simply omitting race and ethnicity from algorithms will ultimately improve care decisions for patients of minoritized racial and ethnic groups.

Dr. Khor and colleagues investigated the performance of four risk prediction models for CRC recurrence using data from 4,230 patients with CRC (53% non-Hispanic white; 22% Hispanic; 13% Black or African American; and 12% Asian, Hawaiian, or Pacific Islander).

The four models were:

• A race-neutral model that explicitly excluded race and ethnicity as a predictor.
• A race-sensitive model that included race and ethnicity.
• A model with two-way interactions between clinical predictors and race and ethnicity.
• Separate models stratified by race and ethnicity.

They found that the race-neutral model had poorer performance (worse calibration, negative predictive value, and false-negative rates) among racial and ethnic minority subgroups, compared with the non-Hispanic subgroup. The false-negative rate for Hispanic patients was 12% vs. 3% for non-Hispanic white patients.

Conversely, including race and ethnicity as a predictor of postoperative cancer recurrence improved the model’s accuracy and increased “algorithmic fairness” in terms of calibration slope, discriminative ability, positive predictive value, and false-negative rates. The false-negative rate for Hispanic patients was 9% and 8% for non-Hispanic white patients.

The inclusion of race interaction terms or using race-stratified models did not improve model fairness, likely due to small sample sizes in subgroups, the authors add.
 

‘No one-size-fits-all answer’

“There is no one-size-fits-all answer to whether race/ethnicity should be included, because the health disparity consequences that can result from each clinical decision are different,” Dr. Khor told this news organization.

“The downstream harms and benefits of including or excluding race will need to be carefully considered in each case,” Dr. Khor said.

“When developing a clinical risk prediction algorithm, one should consider the potential racial/ethnic biases present in clinical practice, which translate to bias in the data,” Dr. Khor added. “Care must be taken to think through the implications of such biases during the algorithm development and evaluation process in order to avoid further propagating those biases.”

The coauthors of a linked commentary say this study “highlights current challenges in measuring and addressing algorithmic bias, with implications for both patient care and health policy decision-making.”

Ankur Pandya, PhD, with Harvard School of Public Health, Boston, and Jinyi Zhu, PhD, with Vanderbilt University, Nashville, Tenn., agree that there is no “one-size-fits-all solution” – such as always excluding race and ethnicity from risk models – to confronting algorithmic bias.

“When possible, approaches for identifying and responding to algorithmic bias should focus on the decisions made by patients and policymakers as they relate to the ultimate outcomes of interest (such as length of life, quality of life, and costs) and the distribution of these outcomes across the subgroups that define important health disparities,” Dr. Pandya and Dr. Zhu suggest.

“What is most promising,” they write, is the high level of engagement from researchers, philosophers, policymakers, physicians and other healthcare professionals, caregivers, and patients to this cause in recent years, “suggesting that algorithmic bias will not be left unchecked as access to unprecedented amounts of data and methods continues to increase moving forward.”

This research was supported by a grant from the National Cancer Institute of the National Institutes of Health. The authors and editorial writers have disclosed no relevant financial relationships.

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

Omitting race and ethnicity from colorectal cancer (CRC) recurrence risk prediction models could decrease their accuracy and fairness, particularly for minority groups, potentially leading to inappropriate care advice and contributing to existing health disparities, new research suggests.

“Our study has important implications for developing clinical algorithms that are both accurate and fair,” write first author Sara Khor, MASc, with University of Washington, Seattle, and colleagues.

“Many groups have called for the removal of race in clinical algorithms,” Dr. Khor said in an interview. “We wanted to better understand, using CRC recurrence as a case study, what some of the implications might be if we simply remove race as a predictor in a risk prediction algorithm.”

Their findings suggest that doing so could lead to higher racial bias in model accuracy and less accurate estimation of risk for racial and ethnic minority groups. This could lead to inadequate or inappropriate surveillance and follow-up care more often in patients of minoritized racial and ethnic groups.

The study was published online in JAMA Network Open.
 

Lack of data and consensus

There is currently a lack of consensus on whether and how race and ethnicity should be included in clinical risk prediction models used to guide health care decisions, the authors note.

The inclusion of race and ethnicity in clinical risk prediction algorithms has come under increased scrutiny, because of concerns over the potential for racial profiling and biased treatment. On the other hand, some argue that excluding race and ethnicity could harm all groups by reducing predictive accuracy and would especially disadvantage minority groups.

It remains unclear whether simply omitting race and ethnicity from algorithms will ultimately improve care decisions for patients of minoritized racial and ethnic groups.

Dr. Khor and colleagues investigated the performance of four risk prediction models for CRC recurrence using data from 4,230 patients with CRC (53% non-Hispanic white; 22% Hispanic; 13% Black or African American; and 12% Asian, Hawaiian, or Pacific Islander).

The four models were:

• A race-neutral model that explicitly excluded race and ethnicity as a predictor.
• A race-sensitive model that included race and ethnicity.
• A model with two-way interactions between clinical predictors and race and ethnicity.
• Separate models stratified by race and ethnicity.

They found that the race-neutral model had poorer performance (worse calibration, negative predictive value, and false-negative rates) among racial and ethnic minority subgroups, compared with the non-Hispanic subgroup. The false-negative rate for Hispanic patients was 12% vs. 3% for non-Hispanic white patients.

Conversely, including race and ethnicity as a predictor of postoperative cancer recurrence improved the model’s accuracy and increased “algorithmic fairness” in terms of calibration slope, discriminative ability, positive predictive value, and false-negative rates. The false-negative rate for Hispanic patients was 9% and 8% for non-Hispanic white patients.

The inclusion of race interaction terms or using race-stratified models did not improve model fairness, likely due to small sample sizes in subgroups, the authors add.
 

‘No one-size-fits-all answer’

“There is no one-size-fits-all answer to whether race/ethnicity should be included, because the health disparity consequences that can result from each clinical decision are different,” Dr. Khor told this news organization.

“The downstream harms and benefits of including or excluding race will need to be carefully considered in each case,” Dr. Khor said.

“When developing a clinical risk prediction algorithm, one should consider the potential racial/ethnic biases present in clinical practice, which translate to bias in the data,” Dr. Khor added. “Care must be taken to think through the implications of such biases during the algorithm development and evaluation process in order to avoid further propagating those biases.”

The coauthors of a linked commentary say this study “highlights current challenges in measuring and addressing algorithmic bias, with implications for both patient care and health policy decision-making.”

Ankur Pandya, PhD, with Harvard School of Public Health, Boston, and Jinyi Zhu, PhD, with Vanderbilt University, Nashville, Tenn., agree that there is no “one-size-fits-all solution” – such as always excluding race and ethnicity from risk models – to confronting algorithmic bias.

“When possible, approaches for identifying and responding to algorithmic bias should focus on the decisions made by patients and policymakers as they relate to the ultimate outcomes of interest (such as length of life, quality of life, and costs) and the distribution of these outcomes across the subgroups that define important health disparities,” Dr. Pandya and Dr. Zhu suggest.

“What is most promising,” they write, is the high level of engagement from researchers, philosophers, policymakers, physicians and other healthcare professionals, caregivers, and patients to this cause in recent years, “suggesting that algorithmic bias will not be left unchecked as access to unprecedented amounts of data and methods continues to increase moving forward.”

This research was supported by a grant from the National Cancer Institute of the National Institutes of Health. The authors and editorial writers have disclosed no relevant financial relationships.

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

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.

On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.

Seven months later, doctors and their patients are facing the unimaginable: In California, Virginia, and everywhere in between, they are being forced into grim contemplation of untested rationing plans for breast, cervical, bladder, ovarian, lung, testicular, and other cancers. Their decisions are likely to result in preventable deaths.

Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.

The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.

But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?

“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”

“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.

“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”

The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.

Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.

“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”

Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.

At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.

On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.

She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”

Doses remained at 80%, she said. Things hadn’t changed 10 days later.
 

Generics manufacturers are pulling out

The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.

As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.

The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.

Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.

The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.

Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.

Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”

Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.

“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
 

Should government step in?

Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.

As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.

Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”

More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.

“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.

Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.

In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.

“It would almost literally be a drop in the bucket.”

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.