Plenty of perks come along with earning a physician’s salary, but a low tax rate isn’t among them. Medscape’s Physicians and Taxes Report 2023 shows that last year, doctors paid an average of nearly $100,000 in state and federal taxes, and three-quarters of them thought that they were paying too much to Uncle Sam. In most cases, it’s impossible to eliminate that tax bill, but physicians told us they have found ways to minimize it.

“The percentage you have to pay in taxes escalates as you earn more money, and most doctors are at the maximum rate,” says Paul Joseph, a certified public accountant and founder of Joseph & Joseph Tax & Payroll in Williamston, Mich. “So every dollar you can deduct from your income is worth more.”

Here’s a look at the seven top tax breaks physician respondents claimed in our tax report, so you can ensure you’re making the most of the tax strategies available to you. To claim most of these options, you’ll need to itemize your deductions when filing your taxes.
 

Contribute to charity

Claimed by 70% of physicians in 2022.

Who’s eligible: Anyone.

How it works: If you itemize your taxes, you can deduct the value of cash, securities, or property donations to 501(c)(3) organizations. You’ll need a receipt from the charity and a third-party appraisal for any property donations worth more than $5,000.

Pro tip: Donating stocks that have appreciated in value can deliver additional tax benefits: You get to write off both the value of the contribution and avoid capital gains taxes that you’d face for selling the security.
 

Contribute to a pre-tax 401(k) account

Claimed by 60% of physicians in 2022.

Who’s eligible: Those who work for a company that sponsors a 401(k) plan.

How it works: Contributions to a 401(k) or 403(b) account come directly out of your paycheck, pre-tax, and grow tax-free until you withdraw them in retirement. Many companies offer a match on contributions. In 2023, you can contribute up to $22,500 ($30,000 if you’re age 50 or older) to a 401(k) account.

Pro tip: If you’re maxing out your 401(k) account, you can stash money in other tax-advantaged accounts such as a health savings account (if you have a high-deductible health plan) or an individual retirement account (IRA). Although employees with access to a 401(k) may not get the pre-tax advantage of the IRA contributions, the money will grow tax-free through retirement, and you may have access to additional investment options unavailable in your workplace plan.

“You want to maximize your retirement contributions,” says Mark Steber, the chief tax information officer for Jackson Hewitt Tax Services. “If you’re not taking full advantage of them, you’re probably leaving some tax dollars on the table.”

If you’re self-employed and don’t have access to a workplace plan, there are several options for tax-advantaged retirement savings, including a SEP IRA and a solo 401(k).
 

Deduct interest on a home mortgage

Claimed by 52% of physicians.

Who’s eligible: Most homeowners who have a mortgage.

How it works: Homeowners can deduct the interest paid on the first $750,000 of their mortgage. (Those who have had the same mortgage since before December 16, 2007, can deduct interest on the first $1 million of their loan.)

Pro tip: If you purchased a home this year and bought points to reduce the rate, you may be able to deduct the cost of those points on your taxes.

Physicians might also be eligible for other home-related tax benefits, such as for green home improvements under the Inflation Reduction Act or for home equity loans used to improve the value of your home.
 

Write off eligible business expenses

Claimed by 46% of physicians.

Who’s eligible: Physicians who own all or a portion of their practice, as well as those who work as consultants or contractors paid with a 1099.

How it works: Doctors who run their business using an LLC or S corporation can itemize the deductions on their Schedule C. There are dozens of deductions that might qualify, including for office space and supplies, medical equipment, uniforms, staff wages and benefits, and state and local tax payments. Physicians who work as consultants can deduct home office expenses, travel costs, and the price of supplies purchased for the job.

“For business expenses, you want to make sure that you’re tracking those expenses on an ongoing basis, rather than trying to reconstruct something at the end of the year from 8 months ago,” Mr. Joseph says. “You want to have a system in place that’s calculating those expenses every single day.”

Pro tip: The Tax Cuts and Jobs Act of 2017 also allows owners of pass-through businesses to deduct up to 20% of their business income.

“Not all physicians will qualify for that, because they are in a service-based business and many of them make too much money, but it’s always a good idea to look at whether that’s something they’re eligible for and make sure that they claim it,” says Eric Bronnenkant, head of tax at New York–based investment company Betterment.
 

Contribute to a 529 college savings plan

Claimed by 27% of physicians.

Who’s eligible: Those who live in the 37 states that offer a credit or deduction for 529 plan contributions.

How it works: The rules and amounts that qualify vary significantly by state. Most states offer benefits for contributions to in-state accounts only, whereas others offer a tax break for contributions to any 529 account.

Although there is no federal income tax benefit for contributions to a 529 plan, the money grows tax-free until tapped for qualified education expenses, which include both private primary and high school tuition and college costs. Starting in 2024, up to $35,000 in unused funds can roll over into a Roth IRA for the beneficiary.

“It’s not just about the immediate deduction with a 529 account,” says Brian Copeland, partner and director of financial planning with Hightower Wealth Advisors in St. Louis. “It’s not saving you a lot on day one; it’s more about as that account grows, you don’t have to pay taxes on it along the way, so you’re sheltering it from taxes for the 18 years you’re saving for your kids’ college.”

Pro tip: Even if you live in a state without a state income tax or without a tax break for 529 contributions, opening an account can be a smart financial move. Because you don’t need to choose an in-state plan for the tax breaks, look for one that offers low fees and investment options that you like.
 

Sell investments at a loss

Claimed by 22% of physicians.

Who’s eligible: Anyone who has sold stocks, mutual funds, or other investments at a loss.

How it works: After selling a security that has lost value, you can deduct the value of that loss on your taxes to offset capital gains in the same year. If you have more losses than gains, you can use the losses to offset up to $3,000 in ordinary income per year. If you have more than $3,000 in losses, you can carry those losses forward to offset future income or capital gains.

Pro tip: In years with a lot of market volatility, such as this one, there’s potential to engage in “tax loss harvesting” in which you intentionally sell securities that have lost value to realize the losses for the tax benefits. Keep in mind that if you sell a security at a loss, you cannot repurchase the same security within 30 days – the IRS sees that as a “wash sale,” which does not qualify for a capital loss for tax purposes.
 

Contribute to a backdoor Roth IRA

Claimed by 20% of physicians.

Who’s eligible: Anyone who wishes to contribute to a Roth IRA but is not allowed to do so because their income is too high.

How it works: High earners typically don’t qualify for contributions to a Roth IRA, in which contributions go in after taxes but grow tax-free and distributions in retirement are also tax-free. But there are no income requirements for making after-tax contributions to a traditional and then converting it to a Roth IRA.

There are, however, complex tax rules for those who also have a traditional IRA that’s funded with pre-tax dollars. If that’s the case, work with a tax pro or financial advisor to determine whether a backdoor Roth conversion is the most tax-efficient approach for your situation.

Pro tip: A growing number of workplace retirement plans now include an option for Roth contributions. There are no income limits on a Roth 401(k), so contributing to that type of an account could be a smart route for taxpayers for whom a backdoor conversion doesn’t make sense.
 

A version of this article appeared on Medscape.com.

Plenty of perks come along with earning a physician’s salary, but a low tax rate isn’t among them. Medscape’s Physicians and Taxes Report 2023 shows that last year, doctors paid an average of nearly $100,000 in state and federal taxes, and three-quarters of them thought that they were paying too much to Uncle Sam. In most cases, it’s impossible to eliminate that tax bill, but physicians told us they have found ways to minimize it.

“The percentage you have to pay in taxes escalates as you earn more money, and most doctors are at the maximum rate,” says Paul Joseph, a certified public accountant and founder of Joseph & Joseph Tax & Payroll in Williamston, Mich. “So every dollar you can deduct from your income is worth more.”

Here’s a look at the seven top tax breaks physician respondents claimed in our tax report, so you can ensure you’re making the most of the tax strategies available to you. To claim most of these options, you’ll need to itemize your deductions when filing your taxes.
 

Contribute to charity

Claimed by 70% of physicians in 2022.

Who’s eligible: Anyone.

How it works: If you itemize your taxes, you can deduct the value of cash, securities, or property donations to 501(c)(3) organizations. You’ll need a receipt from the charity and a third-party appraisal for any property donations worth more than $5,000.

Pro tip: Donating stocks that have appreciated in value can deliver additional tax benefits: You get to write off both the value of the contribution and avoid capital gains taxes that you’d face for selling the security.
 

Contribute to a pre-tax 401(k) account

Claimed by 60% of physicians in 2022.

Who’s eligible: Those who work for a company that sponsors a 401(k) plan.

How it works: Contributions to a 401(k) or 403(b) account come directly out of your paycheck, pre-tax, and grow tax-free until you withdraw them in retirement. Many companies offer a match on contributions. In 2023, you can contribute up to $22,500 ($30,000 if you’re age 50 or older) to a 401(k) account.

Pro tip: If you’re maxing out your 401(k) account, you can stash money in other tax-advantaged accounts such as a health savings account (if you have a high-deductible health plan) or an individual retirement account (IRA). Although employees with access to a 401(k) may not get the pre-tax advantage of the IRA contributions, the money will grow tax-free through retirement, and you may have access to additional investment options unavailable in your workplace plan.

“You want to maximize your retirement contributions,” says Mark Steber, the chief tax information officer for Jackson Hewitt Tax Services. “If you’re not taking full advantage of them, you’re probably leaving some tax dollars on the table.”

If you’re self-employed and don’t have access to a workplace plan, there are several options for tax-advantaged retirement savings, including a SEP IRA and a solo 401(k).
 

Deduct interest on a home mortgage

Claimed by 52% of physicians.

Who’s eligible: Most homeowners who have a mortgage.

How it works: Homeowners can deduct the interest paid on the first $750,000 of their mortgage. (Those who have had the same mortgage since before December 16, 2007, can deduct interest on the first $1 million of their loan.)

Pro tip: If you purchased a home this year and bought points to reduce the rate, you may be able to deduct the cost of those points on your taxes.

Physicians might also be eligible for other home-related tax benefits, such as for green home improvements under the Inflation Reduction Act or for home equity loans used to improve the value of your home.
 

Write off eligible business expenses

Claimed by 46% of physicians.

Who’s eligible: Physicians who own all or a portion of their practice, as well as those who work as consultants or contractors paid with a 1099.

How it works: Doctors who run their business using an LLC or S corporation can itemize the deductions on their Schedule C. There are dozens of deductions that might qualify, including for office space and supplies, medical equipment, uniforms, staff wages and benefits, and state and local tax payments. Physicians who work as consultants can deduct home office expenses, travel costs, and the price of supplies purchased for the job.

“For business expenses, you want to make sure that you’re tracking those expenses on an ongoing basis, rather than trying to reconstruct something at the end of the year from 8 months ago,” Mr. Joseph says. “You want to have a system in place that’s calculating those expenses every single day.”

Pro tip: The Tax Cuts and Jobs Act of 2017 also allows owners of pass-through businesses to deduct up to 20% of their business income.

“Not all physicians will qualify for that, because they are in a service-based business and many of them make too much money, but it’s always a good idea to look at whether that’s something they’re eligible for and make sure that they claim it,” says Eric Bronnenkant, head of tax at New York–based investment company Betterment.
 

Contribute to a 529 college savings plan

Claimed by 27% of physicians.

Who’s eligible: Those who live in the 37 states that offer a credit or deduction for 529 plan contributions.

How it works: The rules and amounts that qualify vary significantly by state. Most states offer benefits for contributions to in-state accounts only, whereas others offer a tax break for contributions to any 529 account.

Although there is no federal income tax benefit for contributions to a 529 plan, the money grows tax-free until tapped for qualified education expenses, which include both private primary and high school tuition and college costs. Starting in 2024, up to $35,000 in unused funds can roll over into a Roth IRA for the beneficiary.

“It’s not just about the immediate deduction with a 529 account,” says Brian Copeland, partner and director of financial planning with Hightower Wealth Advisors in St. Louis. “It’s not saving you a lot on day one; it’s more about as that account grows, you don’t have to pay taxes on it along the way, so you’re sheltering it from taxes for the 18 years you’re saving for your kids’ college.”

Pro tip: Even if you live in a state without a state income tax or without a tax break for 529 contributions, opening an account can be a smart financial move. Because you don’t need to choose an in-state plan for the tax breaks, look for one that offers low fees and investment options that you like.
 

Sell investments at a loss

Claimed by 22% of physicians.

Who’s eligible: Anyone who has sold stocks, mutual funds, or other investments at a loss.

How it works: After selling a security that has lost value, you can deduct the value of that loss on your taxes to offset capital gains in the same year. If you have more losses than gains, you can use the losses to offset up to $3,000 in ordinary income per year. If you have more than $3,000 in losses, you can carry those losses forward to offset future income or capital gains.

Pro tip: In years with a lot of market volatility, such as this one, there’s potential to engage in “tax loss harvesting” in which you intentionally sell securities that have lost value to realize the losses for the tax benefits. Keep in mind that if you sell a security at a loss, you cannot repurchase the same security within 30 days – the IRS sees that as a “wash sale,” which does not qualify for a capital loss for tax purposes.
 

Contribute to a backdoor Roth IRA

Claimed by 20% of physicians.

Who’s eligible: Anyone who wishes to contribute to a Roth IRA but is not allowed to do so because their income is too high.

How it works: High earners typically don’t qualify for contributions to a Roth IRA, in which contributions go in after taxes but grow tax-free and distributions in retirement are also tax-free. But there are no income requirements for making after-tax contributions to a traditional and then converting it to a Roth IRA.

There are, however, complex tax rules for those who also have a traditional IRA that’s funded with pre-tax dollars. If that’s the case, work with a tax pro or financial advisor to determine whether a backdoor Roth conversion is the most tax-efficient approach for your situation.

Pro tip: A growing number of workplace retirement plans now include an option for Roth contributions. There are no income limits on a Roth 401(k), so contributing to that type of an account could be a smart route for taxpayers for whom a backdoor conversion doesn’t make sense.
 

A version of this article appeared on Medscape.com.

Plenty of perks come along with earning a physician’s salary, but a low tax rate isn’t among them. Medscape’s Physicians and Taxes Report 2023 shows that last year, doctors paid an average of nearly $100,000 in state and federal taxes, and three-quarters of them thought that they were paying too much to Uncle Sam. In most cases, it’s impossible to eliminate that tax bill, but physicians told us they have found ways to minimize it.

“The percentage you have to pay in taxes escalates as you earn more money, and most doctors are at the maximum rate,” says Paul Joseph, a certified public accountant and founder of Joseph & Joseph Tax & Payroll in Williamston, Mich. “So every dollar you can deduct from your income is worth more.”

Here’s a look at the seven top tax breaks physician respondents claimed in our tax report, so you can ensure you’re making the most of the tax strategies available to you. To claim most of these options, you’ll need to itemize your deductions when filing your taxes.
 

Contribute to charity

Claimed by 70% of physicians in 2022.

Who’s eligible: Anyone.

How it works: If you itemize your taxes, you can deduct the value of cash, securities, or property donations to 501(c)(3) organizations. You’ll need a receipt from the charity and a third-party appraisal for any property donations worth more than $5,000.

Pro tip: Donating stocks that have appreciated in value can deliver additional tax benefits: You get to write off both the value of the contribution and avoid capital gains taxes that you’d face for selling the security.
 

Contribute to a pre-tax 401(k) account

Claimed by 60% of physicians in 2022.

Who’s eligible: Those who work for a company that sponsors a 401(k) plan.

How it works: Contributions to a 401(k) or 403(b) account come directly out of your paycheck, pre-tax, and grow tax-free until you withdraw them in retirement. Many companies offer a match on contributions. In 2023, you can contribute up to $22,500 ($30,000 if you’re age 50 or older) to a 401(k) account.

Pro tip: If you’re maxing out your 401(k) account, you can stash money in other tax-advantaged accounts such as a health savings account (if you have a high-deductible health plan) or an individual retirement account (IRA). Although employees with access to a 401(k) may not get the pre-tax advantage of the IRA contributions, the money will grow tax-free through retirement, and you may have access to additional investment options unavailable in your workplace plan.

“You want to maximize your retirement contributions,” says Mark Steber, the chief tax information officer for Jackson Hewitt Tax Services. “If you’re not taking full advantage of them, you’re probably leaving some tax dollars on the table.”

If you’re self-employed and don’t have access to a workplace plan, there are several options for tax-advantaged retirement savings, including a SEP IRA and a solo 401(k).
 

Deduct interest on a home mortgage

Claimed by 52% of physicians.

Who’s eligible: Most homeowners who have a mortgage.

How it works: Homeowners can deduct the interest paid on the first $750,000 of their mortgage. (Those who have had the same mortgage since before December 16, 2007, can deduct interest on the first $1 million of their loan.)

Pro tip: If you purchased a home this year and bought points to reduce the rate, you may be able to deduct the cost of those points on your taxes.

Physicians might also be eligible for other home-related tax benefits, such as for green home improvements under the Inflation Reduction Act or for home equity loans used to improve the value of your home.
 

Write off eligible business expenses

Claimed by 46% of physicians.

Who’s eligible: Physicians who own all or a portion of their practice, as well as those who work as consultants or contractors paid with a 1099.

How it works: Doctors who run their business using an LLC or S corporation can itemize the deductions on their Schedule C. There are dozens of deductions that might qualify, including for office space and supplies, medical equipment, uniforms, staff wages and benefits, and state and local tax payments. Physicians who work as consultants can deduct home office expenses, travel costs, and the price of supplies purchased for the job.

“For business expenses, you want to make sure that you’re tracking those expenses on an ongoing basis, rather than trying to reconstruct something at the end of the year from 8 months ago,” Mr. Joseph says. “You want to have a system in place that’s calculating those expenses every single day.”

Pro tip: The Tax Cuts and Jobs Act of 2017 also allows owners of pass-through businesses to deduct up to 20% of their business income.

“Not all physicians will qualify for that, because they are in a service-based business and many of them make too much money, but it’s always a good idea to look at whether that’s something they’re eligible for and make sure that they claim it,” says Eric Bronnenkant, head of tax at New York–based investment company Betterment.
 

Contribute to a 529 college savings plan

Claimed by 27% of physicians.

Who’s eligible: Those who live in the 37 states that offer a credit or deduction for 529 plan contributions.

How it works: The rules and amounts that qualify vary significantly by state. Most states offer benefits for contributions to in-state accounts only, whereas others offer a tax break for contributions to any 529 account.

Although there is no federal income tax benefit for contributions to a 529 plan, the money grows tax-free until tapped for qualified education expenses, which include both private primary and high school tuition and college costs. Starting in 2024, up to $35,000 in unused funds can roll over into a Roth IRA for the beneficiary.

“It’s not just about the immediate deduction with a 529 account,” says Brian Copeland, partner and director of financial planning with Hightower Wealth Advisors in St. Louis. “It’s not saving you a lot on day one; it’s more about as that account grows, you don’t have to pay taxes on it along the way, so you’re sheltering it from taxes for the 18 years you’re saving for your kids’ college.”

Pro tip: Even if you live in a state without a state income tax or without a tax break for 529 contributions, opening an account can be a smart financial move. Because you don’t need to choose an in-state plan for the tax breaks, look for one that offers low fees and investment options that you like.
 

Sell investments at a loss

Claimed by 22% of physicians.

Who’s eligible: Anyone who has sold stocks, mutual funds, or other investments at a loss.

How it works: After selling a security that has lost value, you can deduct the value of that loss on your taxes to offset capital gains in the same year. If you have more losses than gains, you can use the losses to offset up to $3,000 in ordinary income per year. If you have more than $3,000 in losses, you can carry those losses forward to offset future income or capital gains.

Pro tip: In years with a lot of market volatility, such as this one, there’s potential to engage in “tax loss harvesting” in which you intentionally sell securities that have lost value to realize the losses for the tax benefits. Keep in mind that if you sell a security at a loss, you cannot repurchase the same security within 30 days – the IRS sees that as a “wash sale,” which does not qualify for a capital loss for tax purposes.
 

Contribute to a backdoor Roth IRA

Claimed by 20% of physicians.

Who’s eligible: Anyone who wishes to contribute to a Roth IRA but is not allowed to do so because their income is too high.

How it works: High earners typically don’t qualify for contributions to a Roth IRA, in which contributions go in after taxes but grow tax-free and distributions in retirement are also tax-free. But there are no income requirements for making after-tax contributions to a traditional and then converting it to a Roth IRA.

There are, however, complex tax rules for those who also have a traditional IRA that’s funded with pre-tax dollars. If that’s the case, work with a tax pro or financial advisor to determine whether a backdoor Roth conversion is the most tax-efficient approach for your situation.

Pro tip: A growing number of workplace retirement plans now include an option for Roth contributions. There are no income limits on a Roth 401(k), so contributing to that type of an account could be a smart route for taxpayers for whom a backdoor conversion doesn’t make sense.
 

A version of this article appeared on Medscape.com.

The American Academy of Pediatrics recommends against low-carbohydrate diets for most children and adolescents with or at risk for diabetes, according to a new clinical report.

Citing a lack of high-quality data and potential for adverse effects with carbohydrate restriction among younger individuals, lead author Anna Neyman, MD, of Indiana University, Indianapolis, and colleagues suggested that pediatric patients with type 2 diabetes should focus on reducing nutrient-poor carbohydrate intake, while those with type 1 diabetes should only pursue broader carbohydrate restriction under close medical supervision.

“There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth,” the investigators wrote in Pediatrics. “Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes.”

Their new report includes a summary of the various types of carbohydrate-restricted diets, a review of available evidence for these diets among pediatric patients with type 1 and type 2 diabetes, and several practical recommendations based on their findings.

Dr. Neyman and colleagues first noted a lack of standardization in describing the various tiers of carbohydrate restriction; however, they offered some rough guidelines. Compared with a typical, balanced diet, which includes 45%-65% of calories from carbohydrates, a moderately restrictive diet includes 26%-44% of calories from carbohydrates, while a low-carb diet includes less than 26% of calories from carbs. Further down the scale, very low-carb diets and ketogenic diets call for 20-50 g of carbs per day or less than 20 g of carbs per day, respectively.

“There is evidence from adult studies that these diets can be associated with significant weight loss, reduction in insulin levels or insulin requirements, and improvement in glucose control,” the investigators noted. “Nevertheless, there is a lack of long-term safety and efficacy outcomes in youth.”

They went on to cite a range of safety concerns, including “growth deceleration, nutritional deficiencies, poor bone health, nutritional ketosis that cannot be distinguished from ketosis resulting from insulin deficiency, and disordered eating behaviors.”

“Body dissatisfaction associated with restrictive dieting practices places children and adolescents at risk for inadequate dietary intake, excessive weight gain resulting from binge-eating after restricting food intake, and use of harmful weight-control strategies,” the investigators wrote. “Moreover, restrictive dieting practices may negatively impact mental health and self-concept and are directly associated with decreased mood and increased feelings of anxiety.”

Until more evidence is available, Dr. Neyman and colleagues advised adherence to a balanced diet, including increased dietary fiber and reduced consumption of ultra-processed carbohydrates.

“Eliminating sugary beverages and juices significantly improves blood glucose and weight management in children and adolescents,” they noted.

For pediatric patients with type 1 diabetes, the investigators suggested that low-carb and very low-carb diets should only be pursued “under close diabetes care team supervision utilizing safety guidelines.”
 

Lack of evidence is the problem

David Ludwig, MD, PhD, codirector of the New Balance Foundation Obesity Prevention Center, Boston Children’s Hospital, and professor of pediatrics at Harvard Medical School, also in Boston, said the review is “rather general” and “reiterates common, although not always fair, concerns about carbohydrate restriction.”

courtesy Boston Children's Hospital

“The main issue they highlight is the lack of evidence, especially from clinical trials, for a low-carbohydrate diet in children, as related to diabetes,” Dr. Ludwig said in a written comment, noting that this is indeed an issue. “However, what needs to be recognized is that a conventional high-carbohydrate diet has never been shown to be superior in adults or children for diabetes. Furthermore, whereas a poorly formulated low-carb diet may have adverse effects and risks (e.g., nutrient deficiencies), so can a high-carbohydrate diet – including an increase in triglycerides and other risk factors comprising metabolic syndrome.”

He said that the “main challenge in diabetes is to control blood glucose after eating,” and a high-carb makes this more difficult, as it requires more insulin after a meal than a low-carb meal would require, and increases risk of subsequent hypoglycemia.

For those interested in an alternative perspective to the AAP clinical report, Dr. Ludwig recommended two of his recent review articles, including one published in the Journal of Nutrition and another from the Journal of Clinical Investigation. In both, notes the long history of carbohydrate restriction for patients with diabetes, with usage dating back to the 1700s. Although the diet fell out of favor with the introduction of insulin, Dr. Ludwig believes that it needs to be reconsidered, and is more than a passing fad.

“Preliminary research suggests that this dietary approach might transform clinical management and perhaps normalize HbA1c for many people with diabetes, at substantially reduced treatment costs,” Dr. Ludwig and colleagues wrote in the JCI review. “High-quality randomized controlled trials, with intensive support for behavior changes, will be needed to address this possibility and assess long-term safety and sustainability. With total medical costs of diabetes in the United States approaching $1 billion a day, this research must assume high priority.”

This clinical report was commissioned by the AAP. Dr. Ludwig received royalties for books that recommend a carbohydrate-modified diet.

This article was updated 9/20/23.

The American Academy of Pediatrics recommends against low-carbohydrate diets for most children and adolescents with or at risk for diabetes, according to a new clinical report.

Citing a lack of high-quality data and potential for adverse effects with carbohydrate restriction among younger individuals, lead author Anna Neyman, MD, of Indiana University, Indianapolis, and colleagues suggested that pediatric patients with type 2 diabetes should focus on reducing nutrient-poor carbohydrate intake, while those with type 1 diabetes should only pursue broader carbohydrate restriction under close medical supervision.

“There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth,” the investigators wrote in Pediatrics. “Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes.”

Their new report includes a summary of the various types of carbohydrate-restricted diets, a review of available evidence for these diets among pediatric patients with type 1 and type 2 diabetes, and several practical recommendations based on their findings.

Dr. Neyman and colleagues first noted a lack of standardization in describing the various tiers of carbohydrate restriction; however, they offered some rough guidelines. Compared with a typical, balanced diet, which includes 45%-65% of calories from carbohydrates, a moderately restrictive diet includes 26%-44% of calories from carbohydrates, while a low-carb diet includes less than 26% of calories from carbs. Further down the scale, very low-carb diets and ketogenic diets call for 20-50 g of carbs per day or less than 20 g of carbs per day, respectively.

“There is evidence from adult studies that these diets can be associated with significant weight loss, reduction in insulin levels or insulin requirements, and improvement in glucose control,” the investigators noted. “Nevertheless, there is a lack of long-term safety and efficacy outcomes in youth.”

They went on to cite a range of safety concerns, including “growth deceleration, nutritional deficiencies, poor bone health, nutritional ketosis that cannot be distinguished from ketosis resulting from insulin deficiency, and disordered eating behaviors.”

“Body dissatisfaction associated with restrictive dieting practices places children and adolescents at risk for inadequate dietary intake, excessive weight gain resulting from binge-eating after restricting food intake, and use of harmful weight-control strategies,” the investigators wrote. “Moreover, restrictive dieting practices may negatively impact mental health and self-concept and are directly associated with decreased mood and increased feelings of anxiety.”

Until more evidence is available, Dr. Neyman and colleagues advised adherence to a balanced diet, including increased dietary fiber and reduced consumption of ultra-processed carbohydrates.

“Eliminating sugary beverages and juices significantly improves blood glucose and weight management in children and adolescents,” they noted.

For pediatric patients with type 1 diabetes, the investigators suggested that low-carb and very low-carb diets should only be pursued “under close diabetes care team supervision utilizing safety guidelines.”
 

Lack of evidence is the problem

David Ludwig, MD, PhD, codirector of the New Balance Foundation Obesity Prevention Center, Boston Children’s Hospital, and professor of pediatrics at Harvard Medical School, also in Boston, said the review is “rather general” and “reiterates common, although not always fair, concerns about carbohydrate restriction.”

courtesy Boston Children's Hospital

“The main issue they highlight is the lack of evidence, especially from clinical trials, for a low-carbohydrate diet in children, as related to diabetes,” Dr. Ludwig said in a written comment, noting that this is indeed an issue. “However, what needs to be recognized is that a conventional high-carbohydrate diet has never been shown to be superior in adults or children for diabetes. Furthermore, whereas a poorly formulated low-carb diet may have adverse effects and risks (e.g., nutrient deficiencies), so can a high-carbohydrate diet – including an increase in triglycerides and other risk factors comprising metabolic syndrome.”

He said that the “main challenge in diabetes is to control blood glucose after eating,” and a high-carb makes this more difficult, as it requires more insulin after a meal than a low-carb meal would require, and increases risk of subsequent hypoglycemia.

For those interested in an alternative perspective to the AAP clinical report, Dr. Ludwig recommended two of his recent review articles, including one published in the Journal of Nutrition and another from the Journal of Clinical Investigation. In both, notes the long history of carbohydrate restriction for patients with diabetes, with usage dating back to the 1700s. Although the diet fell out of favor with the introduction of insulin, Dr. Ludwig believes that it needs to be reconsidered, and is more than a passing fad.

“Preliminary research suggests that this dietary approach might transform clinical management and perhaps normalize HbA1c for many people with diabetes, at substantially reduced treatment costs,” Dr. Ludwig and colleagues wrote in the JCI review. “High-quality randomized controlled trials, with intensive support for behavior changes, will be needed to address this possibility and assess long-term safety and sustainability. With total medical costs of diabetes in the United States approaching $1 billion a day, this research must assume high priority.”

This clinical report was commissioned by the AAP. Dr. Ludwig received royalties for books that recommend a carbohydrate-modified diet.

This article was updated 9/20/23.

The American Academy of Pediatrics recommends against low-carbohydrate diets for most children and adolescents with or at risk for diabetes, according to a new clinical report.

Citing a lack of high-quality data and potential for adverse effects with carbohydrate restriction among younger individuals, lead author Anna Neyman, MD, of Indiana University, Indianapolis, and colleagues suggested that pediatric patients with type 2 diabetes should focus on reducing nutrient-poor carbohydrate intake, while those with type 1 diabetes should only pursue broader carbohydrate restriction under close medical supervision.

“There are no guidelines for restricting dietary carbohydrate consumption to reduce risk for diabetes or improve diabetes outcomes in youth,” the investigators wrote in Pediatrics. “Thus, there is a need to provide practical recommendations for pediatricians regarding the use of low-carbohydrate diets in patients who elect to follow these diets, including those with type 1 diabetes and for patients with obesity, prediabetes, and type 2 diabetes.”

Their new report includes a summary of the various types of carbohydrate-restricted diets, a review of available evidence for these diets among pediatric patients with type 1 and type 2 diabetes, and several practical recommendations based on their findings.

Dr. Neyman and colleagues first noted a lack of standardization in describing the various tiers of carbohydrate restriction; however, they offered some rough guidelines. Compared with a typical, balanced diet, which includes 45%-65% of calories from carbohydrates, a moderately restrictive diet includes 26%-44% of calories from carbohydrates, while a low-carb diet includes less than 26% of calories from carbs. Further down the scale, very low-carb diets and ketogenic diets call for 20-50 g of carbs per day or less than 20 g of carbs per day, respectively.

“There is evidence from adult studies that these diets can be associated with significant weight loss, reduction in insulin levels or insulin requirements, and improvement in glucose control,” the investigators noted. “Nevertheless, there is a lack of long-term safety and efficacy outcomes in youth.”

They went on to cite a range of safety concerns, including “growth deceleration, nutritional deficiencies, poor bone health, nutritional ketosis that cannot be distinguished from ketosis resulting from insulin deficiency, and disordered eating behaviors.”

“Body dissatisfaction associated with restrictive dieting practices places children and adolescents at risk for inadequate dietary intake, excessive weight gain resulting from binge-eating after restricting food intake, and use of harmful weight-control strategies,” the investigators wrote. “Moreover, restrictive dieting practices may negatively impact mental health and self-concept and are directly associated with decreased mood and increased feelings of anxiety.”

Until more evidence is available, Dr. Neyman and colleagues advised adherence to a balanced diet, including increased dietary fiber and reduced consumption of ultra-processed carbohydrates.

“Eliminating sugary beverages and juices significantly improves blood glucose and weight management in children and adolescents,” they noted.

For pediatric patients with type 1 diabetes, the investigators suggested that low-carb and very low-carb diets should only be pursued “under close diabetes care team supervision utilizing safety guidelines.”
 

Lack of evidence is the problem

David Ludwig, MD, PhD, codirector of the New Balance Foundation Obesity Prevention Center, Boston Children’s Hospital, and professor of pediatrics at Harvard Medical School, also in Boston, said the review is “rather general” and “reiterates common, although not always fair, concerns about carbohydrate restriction.”

courtesy Boston Children's Hospital

“The main issue they highlight is the lack of evidence, especially from clinical trials, for a low-carbohydrate diet in children, as related to diabetes,” Dr. Ludwig said in a written comment, noting that this is indeed an issue. “However, what needs to be recognized is that a conventional high-carbohydrate diet has never been shown to be superior in adults or children for diabetes. Furthermore, whereas a poorly formulated low-carb diet may have adverse effects and risks (e.g., nutrient deficiencies), so can a high-carbohydrate diet – including an increase in triglycerides and other risk factors comprising metabolic syndrome.”

He said that the “main challenge in diabetes is to control blood glucose after eating,” and a high-carb makes this more difficult, as it requires more insulin after a meal than a low-carb meal would require, and increases risk of subsequent hypoglycemia.

For those interested in an alternative perspective to the AAP clinical report, Dr. Ludwig recommended two of his recent review articles, including one published in the Journal of Nutrition and another from the Journal of Clinical Investigation. In both, notes the long history of carbohydrate restriction for patients with diabetes, with usage dating back to the 1700s. Although the diet fell out of favor with the introduction of insulin, Dr. Ludwig believes that it needs to be reconsidered, and is more than a passing fad.

“Preliminary research suggests that this dietary approach might transform clinical management and perhaps normalize HbA1c for many people with diabetes, at substantially reduced treatment costs,” Dr. Ludwig and colleagues wrote in the JCI review. “High-quality randomized controlled trials, with intensive support for behavior changes, will be needed to address this possibility and assess long-term safety and sustainability. With total medical costs of diabetes in the United States approaching $1 billion a day, this research must assume high priority.”

This clinical report was commissioned by the AAP. Dr. Ludwig received royalties for books that recommend a carbohydrate-modified diet.

This article was updated 9/20/23.

TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

In 2020, U.S. counties that were without psychiatric care or broadband coverage had significantly more drug overdose deaths and completed suicides, compared with other counties, new research shows.

METHODOLOGY:

• In the United States, there is a severe lack of psychiatrists and access to mental health care. In 2019, 21.3 million U.S. residents were without broadband access. These patients were forced either to use telephone consultation or to not use telehealth services at all, although use of telehealth during COVID-19 somewhat improved access to psychiatric care.
• For the study, researchers gathered sociodemographic and other county-level information from the American Community Survey. They also used data on the psychiatrist workforce from the Health Resources and Services Administration (HRSA) Area Health Resources Files.
• Information on broadband Internet coverage came from the Federal Communications Commission, and measures of mental health outcomes were from the Centers for Disease Control and Prevention.

TAKEAWAY:

• The study identified 596 counties (19% of all U.S. counties) that were without psychiatrists and in which there was inadequate broadband coverage. The population represented 10.5 million residents.
• Compared with other counties, those with lack of coverage were more likely to be rural (adjusted odds ratio, 3.05; 95% confidence interval, 2.41-3.84), to have higher unemployment (aOR, 1.12; 95% CI, 1.02-1.24), and to have higher uninsurance rates (aOR, 1.03; 95% CI, 1.00-1.06). In those counties, there were also fewer residents with a bachelor’s degree (aOR, 0.92; 95% CI, 0.90-0.94) and fewer Hispanics (aOR 0.98; 95% CI, 0.97-0.99), although those counties were not designated by the HRSA as having a psychiatrist shortage. That designation brings additional funding for the recruitment of clinicians.
• After adjustment for sociodemographic factors, counties without psychiatrists and broadband had significantly higher rates of adult depression, frequent mental distress, drug overdose mortality, and completed suicide, compared with other counties.
• Further analysis showed that the adjusted difference remained statistically significant for drug overdose mortality per 100,000 (9.2; 95% CI, 8.0-10.5, vs. 5.2; 95% CI, 4.9-5.6; P < .001) and completed suicide (10.6; 95% CI, 8.9-12.3, vs. 7.6; 95% CI, 7.0-8.2; P < .001), but not for the other two measures.

IN PRACTICE:

“Our finding suggests that lacking access to virtual and in-person psychiatric care continues to be a key factor associated with adverse outcomes,” the investigators write. They note that federal and state-level investments in broadband and the psychiatric workforce are needed.

SOURCE:

The study was conducted by Tarun Ramesh, BS, department of population medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, and colleagues. It was published online as a research letter in JAMA Network Open.

LIMITATIONS:

The investigators did not consider whether recent legislation, including the Consolidated Appropriations Act of 2021 and the American Rescue Plan, which expanded psychiatry residency slots and broadband infrastructure, reduces adverse outcomes, something the authors say future research should examine.

DISCLOSURES:

The study received support from the National Institutes of Health, including the National Institute on Minority Health and Health Disparities and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.

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

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

The American College of Physicians has issued an updated version of its living, rapid practice point guideline on the best treatment options for outpatients with confirmed COVID-19 in the era of the dominant Omicron variant of SARS-CoV-2. The recommendations in version 2 apply to persons presenting with mild to moderate infection and symptom onset in the past 5 days who are at high risk for progression to severe disease and potential hospitalization or death.

Version 1 appeared in late 2022.

While outpatient management is appropriate for most patients, treatment should be personalized and based on careful risk stratification and informed decision-making, said the guideline authors, led by Amir Qaseem, MD, PhD, MHA, vice president of clinical policy and the Center for Evidence Reviews at the ACP in Philadelphia.
 

Practice points

• Consider the oral antivirals nirmatrelvir-ritonavir (Paxlovid) or molnupiravir (Lagevrio) for symptomatic outpatients with confirmed mild to moderate COVID-19 who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease.

New evidence for the Omicron variant suggests a possible net benefit of the antiviral molnupiravir versus standard or no treatment in terms of reducing recovery time if treatment is initiated within 5 days of symptom onset. Nirmatrelvir-ritonavir was associated with reductions in COVID-19 hospitalization and all-cause mortality.

“The practice points only address [whether] treatments work compared to placebo, no treatment, or usual care,” cautioned Linda L. Humphrey, MD, MPH, MACP, chair of the ACP’s Population Health and Medical Science Committee and a professor of medicine at Oregon Health and Science University VA Portland Health Care System. The ACP continues to monitor the evidence. “Once enough evidence has emerged, it will be possible to compare treatments to each other. Until that time we are unable to determine if there is an advantage to using one treatment over another.”

• Do not use the antiparasitic ivermectin (Stromectol) or the monoclonal antibody sotrovimab (Xevudy) to treat this patient population. “It is not expected to be effective against the Omicron variant,” Dr. Humphrey said.

There was no evidence to support the use of medications such as corticosteroids, antibiotics, antihistamines, SSRIs, and multiple other agents.

“The guideline is not a departure from previous knowledge and reflects what appears in other guidelines and is already being done generally in practice,” said Mirella Salvatore, MD, an associate professor of medicine and population health sciences at Weill Cornell Medicine, New York, who was not involved in the ACP statement. It is therefore unlikely the recommendations will trigger controversy or negative feedback, added Dr. Salvatore, who is also a spokesperson for the Infectious Diseases Society of America. “We believe that our evidence-based approach, which considers the balance of benefits and harms of various treatments, will be embraced by the physician community,” Dr. Humphrey said.

The updated recommendations are based on new data from the evidence review of multiple treatments, which concluded that both nirmatrelvir-ritonavir and molnupiravir likely improve outcomes for outpatients with mild to moderate COVID-19. The review was conducted after the emergence of the Omicron variant by the ACP Center for Evidence Reviews at Cochrane Austria/University for Continuing Education Krems (Austria).


 

Review details

Inclusion criteria were modified to focus on the Omicron variant by limiting eligible studies to only those enrolling patients on or after Nov. 26, 2021. The investigators included two randomized controlled trials and six retrospective cohort studies and ranked quality of evidence for the effectiveness of the following treatments, compared with usual care or no treatment: azithromycin, camostat mesylate, chloroquine-hydroxychloroquine, chlorpheniramine, colchicine, convalescent plasma, corticosteroids, ensitrelvir, favipiravir, fluvoxamine, ivermectin, lopinavir-ritonavir, molnupiravir, neutralizing monoclonal antibodies, metformin, niclosamide, nitazoxanide, nirmatrelvir-ritonavir, and remdesivir.

It compared results for all-cause and COVID-specific mortality, recovery, time to recovery, COVID hospitalization, and adverse and serious adverse events.

Nirmatrelvir-ritonavir was associated with a reduction in hospitalization caused by COVID-19 of 0.7% versus 1.2% (moderate certainty of evidence [COE]) and a reduction in all-cause mortality of less than 0.1% versus 0.2% (moderate COE).

Molnupiravir led to a higher recovery rate of 31.8% versus 22.6% (moderate COE) and a reduced time to recovery of 9 versus 15 median days (moderate COE). It had no effect, however, on all-cause mortality: 0.02% versus 0.04% (moderate COE). Nor did it affect the incidence of serious adverse events: 0.4% versus 0.3% (moderate COE).

“There have been no head-to-head comparative studies of these two treatments, but nirmatrelvir-ritonavir appears to be the preferred treatment,” Dr. Salvatore said. She noted that molnupiravir cannot be used in pregnant women or young persons under age 18, while nirmatrelvir-ritonavir carries the risk of drug interactions. Viral rebound and recurrence of symptoms have been reported in some patients receiving nirmatrelvir-ritonavir.

In other review findings, ivermectin had no effect on time to recovery (moderate COE) and adverse events versus placebo (low COE). Sotrovimab resulted in no difference in all-cause mortality, compared with no treatment (low COE). There were no eligible studies for all of the other treatments of interest nor were there any that specifically evaluated the benefits and harms of treatments for the Omicron variant.

The panel pointed to the need for more evaluation of the efficacy, effectiveness, and comparative effectiveness, as well as harms of pharmacologic and biologic treatments of COVID-19 in the outpatient setting, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.

Another area requiring further research is the effectiveness of retreatment in patients with previous COVID-19 infection. Subgroup analyses are also needed to assess whether the efficacy and effectiveness of outpatient treatments vary by age, sex, socioeconomic status, and comorbid conditions – or by SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.

Dr. Salvatore agreed that more research is needed in special convalescent groups. “For instance, those with cancer who are immunocompromised may need longer treatment and adjunctive treatment with convalescent plasma. But is difficult to find a large enough study with 5,000 immunocompromised patients.”

Financial support for the development of the practice points came exclusively from the ACP operating budget. The evidence review was funded by the ACP. The authors disclosed no relevant high-level competing interests with regard to this guidance, although several authors reported intellectual interests in various areas of research. Dr. Salvatore disclosed no conflicts of interest relevant to her comments but is engaged in influenza research for Genentech.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

MDedge: What were the earliest acute care medications available for migraine?

Dr. Rapoport: In the 1940s, ergotamine tartrate tablets and sublingual tablets were introduced as therapy to treat migraine. They were not that well absorbed, caused nausea, and were not very effective—but they were the only treatment option. Then, beginning in the early 1990s, doctors began prescribing a class of medications called triptans to stop a migraine in progress. Patients are instructed to quickly take the triptan as soon as they know it is or will be a migraine headache; if they wait too long, it may not work as well—or at all. If they don’t have any improvement in 2 hours, they are encouraged to repeat the dosage, even though it often does not work well.

As I strongly recommend to my patients, triptans should not be used more than 2 days per week. An average of 3 days per week or more is too much, and triptan medications can cause medication overuse headache (MOH). If the patient develops MOH, they usually have more headaches rather than fewer—and the medication stops working well.

These medicines work in about 60% of patients and not so well in the other 40%. They do cause side effects in certain people, which may include some pain in their chest or neck muscles and  constriction of blood vessels. Some patients also feel a warm-to-hot feeling all over, tingling sensation, drowsiness, dizziness, and other side effects. Some will experience these side effects but continue to take these medications because they work; however, some patients can’t take them because they find the side effects to be too bothersome.

The first triptan to be marketed (in 1992) was a 6-mg, self-injected, subcutaneous injection of sumatriptan (Imitrex). Injection was the only available delivery method for a triptan until 1994, when the tablet form became available.

Typically, patients who hadn’t taken the sumatriptan injections preferred to start with the tablets, but the patients who had been taking the injection form were used to it and preferred to keep taking it. They knew that it worked well, and if they had mild side effects, they weren’t troubled by them. However, most new patients, when given a choice, asked for the tablet instead of the injection. In 1996, sumatriptan nasal spray was introduced, which is inconsistently absorbed, and patients report it does not taste or smell good. 

Within a few years, more triptan tablets became available: zolmitriptan (1997), rizatriptan (1998), naratriptan (1998), almotriptan and frovatriptan (2001), and eletriptan (2002). An oral film form of rizatriptan (RizaFilm) was FDA-approved in 2023. The zolmitriptan nasal spray was approved in 2003 and is easy to use, with few adverse effects and good efficacy. There is also a new type of sumatriptan nasal spray (approved in 2019) with a permeation enhancer that makes it adhere to the mucous membranes of the nose and allows it to work faster. It does not have the same disliked taste and smell that caused patients to avoid other similar medications. However, most patients still seem to prefer triptans in tablet form over the nasal spray or injection. 

Now there are a total of 2 triptan nasal sprays and 7 triptans in tablet form, 2 of which are orally disintegrating tablets (ODT), and there are several sumatriptan injections available that come in 3- 4- or 6-mg dosages. 

Do you prefer to prescribe a particular triptan medication to your patients, and if so, why?

Of the different forms of triptans (nasal sprays, tablets, and injections), my favorite is the nasal spray form of zolmitriptan 5 mg (it also comes in 2.5-mg doses, which I sometimes prescribe to pediatric patients). I prefer it because of how quickly it works to provide my patients relief from migraine. All tablets must go down the esophagus, into the stomach, then into the small intestine to the level of the jejunum, where it is absorbed. It then goes to the liver, where it is metabolized, and then (once it finally gets into the bloodstream), it starts working. By contrast, when medication is administered into the nasal cavity, it is quickly absorbed from the mucous membrane and enters the bloodstream there and begins working faster than the tablet does. Zolmitriptan also has fewer side effects than the tablet, and my patients appreciate that. If tablets of triptans do not work, I switch to zolmitriptan nasal spray and, in rare situations, the sumatriptan injection.

When would I switch a patient from a triptan any of the new classes of medicines? 

If a patient takes a triptan at the first sign of migraine and it doesn’t begin to work for 2 hours, that is taking too long. If the triptan relieves only 50% of the head pain, there is a good chance that the headache will linger and later return with a vengeance. That would make me consider switching a patient to one of the other types of migraine medications. Even if the patient repeats the triptan at 2 hours after the first one, it probably won’t be very effective at that point. I also want to know if a patient experiences any side effects from the triptan. If they say it works, but they get chest pain, drowsiness, or dizziness and can’t function, I may want to switch them to a newer medication.

Triptans can stimulate the serotonin 1B receptors on the nerves on the small blood vessels in various parts of the body. Because of that, they may constrict blood vessels, such as the coronary arteries in the heart or others in brain, which could possibly lead to a heart attack or stroke or hypertension in some patients. I might switch a medication from a triptan for a patient who is older (over 50), has high blood pressure or cholesterol, has obesity, does not regularly exercise, or has a family history of a heart attack or stroke at an early age. You really don’t want to constrict blood vessels in these patients and should consider a newer therapy.

Can you tell us more about the nasal sprays for acute care of migraine?

Other than the standard sumatriptan nasal spray, the half-dose of sumatriptan nasal spray with a permeation enhancer, and zolmitriptan nasal spray, there are 2 additional options on the market. They are both dihydroergotamine (DHE) mesylate, an ergot alkaloid liquid nasal spray. They are identical chemicals with different devices that produce the sprays. The older DHE nasal spray is called Migranal; it is used 1 time in each nostril, then 15 minutes later is repeated. I feel like it takes too long to get the medicine into the bloodstream because the nasal spray only emits a gentle spray that lays on the bottom of the nose. It doesn’t get to the top or back of the nasal cavity, where there are more blood vessels, which would result in better absorption and efficacy. The second nasal spray is called Trudhesa, which came out just a few years ago when another company took the same exact chemical entity and delivered it with a bigger sprayer that fires it up to the top and back of the nose, where it is better absorbed. That nasal spray seems to work better than the old nasal spray. We don’t have data showing how much better it works than the other, but patients tend to like it more. We may also see a fine DHE nasal powder soon, which may take slightly longer to work but with good efficacy that lasts longer.

Have any adverse events been reported with the DHE nasal sprays for migraine?

A patient may experience some pain or burning in the nose, have a funny taste in the mouth, or even experience a change in the way a food tastes for a while after taking the DHE nasal spray. It could also cause some chest discomfort because it stimulates the same receptors as the triptans, plus other receptors as well. 

Are there any newer acute care medications for migraine?

There are 2 newer groups of migraine medications that have come out within the past few years: gepants and a ditan. There are 2 gepants currently available. The first one to be FDA-approved for acute care of migraine (in 2019) was ubrogepant (Ubrelvy), and the second gepant, rimegepant (Nurtec), was approved in 2020. They both work approximately the same way, but they may cause different adverse events. They both sit on the calcitonin gene-related peptide (CGRP) receptors. These receptors are all over the body and the brain, but the place where researchers believe they work most effectively is on the first branch of the trigeminal nerve between the brainstem and the meninges. This is the trigeminovascular system. It works outside of the central nervous system and modulates what goes on inside the central nervous system.

Ubrogepant is a regular tablet that has 2 sizes, 50 and 100 mg. I might start a patient on a 50-mg tablet, and I will instruct them to take another dose (up to 200 mg a day) if they have not improved in 2 hours. Rimegepant comes only as a 75-mg ODT, or fast melt tablet which means a patient can put it on their tongue and they don’t need water with it. For example, if a patient is stuck on an interstate in a traffic jam at rush hour, is getting a terrible headache, and doesn’t happen to have water, they could just place the tablet it in their mouth, where it will dissolve in 5 to 10 seconds. A second dose doesn’t seem to be necessary; if the headache persists, I will switch to another type of medication that day.

The other category of acute migraine medicine that has been approved in the last few years is called a ditan. Only 1 ditan in the class is available right now, lasmiditan (Reyvow). It was FDA-approved in 2019 and works a little bit differently from the gepants, as it’s more like a triptan. Instead of stimulating the serotonin 1B and 1D receptors, it stimulates the serotonin 1F receptor. This is important because it doesn’t stimulate the 1B receptor and therefore doesn’t constrict blood vessels. The one good thing about this medication is it can be prescribed to an older patient or a patient that has any kind of coronary artery risk factors like smoking or obesity. It does enter the central nervous system to begin working, and when a drug does that, it’s more likely to have different side effects, such as dizziness or drowsiness—and this medication does cause both. The drug works well, but the side effects must be carefully observed. Patients are advised not to drive a car or operate machinery for 8 hours after taking this drug.

The advancements in the pharmacologic treatment options for the acute care of migraine offer a wide range of options for patients with migraine—allowing for more personalized and effective approaches for relief, with fewer adverse events than ever before.

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

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

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

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

TOPLINE:

Prevalence of sexual dysfunction in schizophrenia patients remains high, with improved screening and treatment of depression possibly improving sexual health of these patients, results of a systematic review and meta-analysis show.

METHODOLOGY:

• Data on sexual dysfunction prevalence in people with schizophrenia should be updated because the only meta-analysis on this topic was published over 10 years ago, and factors that could explain the heterogeneity of sexual dysfunctions in schizophrenia also need reexamining.
• After carrying out a literature search for observational studies reporting prevalence of sexual dysfunction in outpatients receiving treatment for schizophrenia or schizoaffective disorder, researchers included 72 studies with 21,076 patients from 33 countries published between 1979 and 2021 in their review.
• They determined pooled estimates of sexual dysfunction prevalence in men and women and of each specific dysfunction.

TAKEAWAY:

• Pooled estimates for global prevalence were: 56.4% for sexual dysfunctions (95% confidence interval, 50.5-62.2), 40.6% for loss of libido (95% CI, 30.7-51.4), 28.0% for orgasm dysfunction (95% CI, 18.4-40.2), and 6.1% for genital pain (95% CI, 2.8-12.7), with study design, sociodemographic data, and other factors associated with the high heterogeneity of sexual dysfunctions.
• In men, estimates were: 55.7% for sexual dysfunction (95% CI, 48.1-63.1), 44.0% for erectile dysfunction (95% CI, 33.5-55.2), and 38.6% ejaculation dysfunction (95% CI, 26.8-51.8).
• In women, estimates were: 60.0% for sexual dysfunction (95% CI, 48.0-70.8), 25.1% for amenorrhea (95% CI, 17.3-35.0), and 7.7% for galactorrhea (95% CI, 3.7-15.3).
• Studies with the highest proportion of antidepressant prescriptions reported lower rates of sexual dysfunctions.

IN PRACTICE:

The review shows that sexual dysfunction is “extremely frequent” in schizophrenia and uncovers “important evidence” suggesting that better screening and treatment of depression “may be an effective strategy to improve sexual health in patients with schizophrenia,” write the authors.

SOURCE:

The study was carried out by Théo Korchia, MD, Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, CEReSS: Health Service Research and Quality of Life Center, France, and colleagues. It was published online in JAMA Psychiatry.

LIMITATIONS:

Most factors known to increase sexual dysfunction, including hypertension, diabetes, obesity, smoking, and sleep disorders, were poorly explored in the included studies. Results may not be extrapolated to continents such as Africa and Polynesia because they were underrepresented in the review. The presence of publication bias in the meta-analysis can’t be entirely ruled out. Heterogeneity or methodological differences may have contributed to the observed results.

DISCLOSURES:

The authors have no relevant conflict of interest.

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

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

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

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

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

I’m a creature of habit. I suspect most of us are.

One can of Diet Coke on the drive to my office. Turn on the WiFi and air conditioning. Fire up the computer and unload my briefcase. Then do online refills, check the Astronomy Picture of the Day, look over the day’s schedule, turn on the Keurig, and make one cup of coffee. And so on.

I’m sure most of us have similar routines. Our brains are probably wired that way for survival, though the reasons aren’t the same anymore. Once it was get up, look outside the cave for predators, make sure the tribe is all accounted for, go to the stream for water, look for berries.

The fact is that automatic habits are critical for everything we do. Driving a car is really a series of repetitive tasks. Being able to put most of the ride on our brain’s autopilot allows us to move our attention to scanning the surroundings for changes, and to think about other items such as wonder what to do for dinner and if I remembered to turn off theWiFi and Keurig.

The practice of medicine is similar. Some things are internalized. Watching patients walk back to my office, looking at their hands as they fill out forms, hearing them introduce themselves, and other things that we subconsciously process as part of the exam before we’ve even officially begun the appointment. I quietly file such things away to be used later in the visit.

It certainly wasn’t always that way. In training we learn to filter out signal from noise, because the information available is huge. We all read tests of some sort. When I began reading EEGs, the images and lines were overwhelming, but with time and experience I became skilled at whittling down the mass of information into the things that really needed to be noted so I could turn pages faster (yes, youngsters, EEGs used to be on paper). Now, scanning the screen becomes a background habit, with the brain focusing more on things that stand out (or going back to thinking about what to do for dinner).

Over the millennia we’ve changed daily routines from something critical for survival to what we need for individual success in a chosen field. The brain in this way is the ultimate Swiss Army Knife – many tools available, but how we adapt and use them for our individual needs is variable.

Which is pretty impressive, actually. In the era of AI and computers, we each come with a (roughly) 2.5-petabyte hard drive that’s not only capable of storing all that information, but figuring out how to use it when we need to. The process is so smooth that we’re rarely aware of it. But what a marvel it is.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

The first randomized trial to evaluate postprocedural anticoagulation (PPA) in patients undergoing a primary percutaneous coronary intervention (PCI) for an ST-segment elevation myocardial infarction (STEMI) did not associate significant benefit – or significant harm – with any of the three tested regimens relative to placebo.

There has been a signal from nonrandomized studies that PPA reduces the risk for ischemic events, but no controlled prospective trials have evaluated the risk-benefit relationship in STEMI patients, said Yan Yan, MD, a researcher in Beijing Anzhen Hospital.

The results of the randomized trial, called RIGHT, were presented at the annual congress of the European Society of Cardiology by Dr. Yan, on behalf of a team of coinvestigators led by Nie Shaoping, MD, PhD, a cardiologist affiliated with Capital Medical University, Beijing.

The bottom line is that “routine PPA with low-dose anticoagulation after primary PCI in STEMI patients is safe, but it does not improve ischemic outcome at 30 days,” Dr. Yan concluded.
 

Objective study

In her presentation, Dr. Yan explained that an objective study has been needed to validate the common use of empirically administered PPA. According to Dr. Yan, PPA is being offered to up to 40% of STEMI patients in Europe, with even higher rates in China.

In the investigator-initiated RIGHT trial, 2,856 STEMI patients undergoing PCI were randomized to PPA or placebo in a 1:1 ratio. In the PPA arm, patients received one of three low-dose anticoagulation regimens over 48 hours or until discharge if this was longer: 0.2 mg/kg per hour of bivalirudin administered intravenously; 40 mg of enoxaparin administered subcutaneously; or 10 U/kg per hour of unfractionated heparin (UFH) to maintain an activated coagulation time between 150 and 200 seconds.

Each of the 53 participating Chinese centers selected one of the anticoagulation regimens. Matching placebos were employed in the double-blind design. All received bivalirudin anticoagulation during PCI. Exclusion criteria included unstable disease, such as cardiogenic shock, prior coronary artery bypass grafting, or an indication for anticoagulation other than PPA.

For the composite primary endpoint of all-cause death, nonfatal MI, nonfatal stroke, stent thrombosis, or urgent revascularization at 30 days, there was no difference between PPA and placebo. The event rate in both arms was 2.5%.

There were also no significant differences between PPA and placebo for any of the secondary ischemic endpoints, which included the individual components of the primary endpoint and cardiovascular death.

For the primary safety endpoint of Bleeding Academic Research Consortium (BARC) grade 3-5 bleeding, the slight increase in events among those in the placebo group did not approach statistical significance (P = .551). On other definitions of bleeding, which were secondary endpoints, PPA and placebo also did not differ significantly.

Compared for safety, the three anticoagulation regimens performed similarly with no significant interaction for the primary endpoint (P = .679).

For efficacy, the differences did range sufficiently to produce a significant interaction (P = .01) with enoxaparin appearing to be more effective, UFH less effective, and bivalirudin falling in between. This led Dr. Yan to speculate that the three anticoagulants “may not be equivalent,” although she said larger trials are needed to explore potential differences.
 

Design flawed?

The ESC-invited discussant, Pascal Vranckx, MD, PhD, medical director, cardiac critical care services, Hartcentrum Hasselt, Belgium, liked the question being asked in the study, but concluded that the design was flawed.

“There are a variety of anticoagulants employed in a variety of doses [for PPA] but we have very limited data. The research question is totally appropriate,” he said. However, he asked, “What went wrong? Was it the drugs, the trial, or both?”

The problem, he thinks, is the dose. Much of the design of RIGHT was based on the 2015 MATRIX trial, which did show a benefit from a single dose of bivalirudin following PCI relative to two other comparators. In that study, STEMI patients randomized to bivalirudin received a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg per hour for at least 4 hours. The comparators were UFH or a control arm of low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors.

At 30 days, bivalirudin was associated with a 40% reduction (hazard ratio, 0.60; P = .001) relative to control for the composite primary endpoint of death or bleeding. Dr. Vranckx pointed out that MATRIX was a trial of a single-dose prolongation of PPA, whereas RIGHT was “a prolongation of a prolongation,” but he believes MATRIX data support higher doses of anticoagulation, particularly of bivalirudin.

“Perhaps low dose bivalirudin is not the way to go,” he speculated.

He further advised the authors to reevaluate the expected benefit from PPA following STEMI. In MATRIX, the risk for events was highly concentrated in the immediate period after PCI, suggesting that the opportunity to reduce risk is much lower as anticoagulation is prolonged. He suggested that the low number of events in RIGHT are consistent with the diminishing risk for events over time.

Nevertheless, Dr. Vranckx praised the authors for addressing a research question that is “timely and highly relevant.” He called the data “important” by drawing attention to a potential target for risk reduction, and encouraged additional trials to determine what PPA strategy, if any, can further reduce early ischemic events after PCI.

Dr. Yan and colleagues report financial relationships with Abbott, Boston Scientific, East China Pharmaceuticals, Saniju Medical and Pharmaceuticals, and Jiangsu Hengrui Pharmaceuticals, which provided funding for this study. Dr. Vranckx reports no potential conflicts of interest.

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

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.

Most patients with non–small cell lung cancer (NSCLC) who are long-term responders to immunotherapy will continue receiving treatment beyond 2 years. However, the best available evidence to date indicates that receiving immunotherapy after this 2-year mark likely offers no survival benefit.

Given the data, why do many clinicians keep having their patients receive immunotherapy beyond 2 years?

Is it an overabundance of caution? A desire for more definitive data? Or is it simply a judgment call oncologists make on the basis of the individual patient?

Lova Sun, MD, MSCE, of the University of Pennsylvania in Philadelphia, believes the general inconsistency between the data and clinical practice “likely reflects significant hesitation on the part of clinicians, patients, or both to stop a treatment that is still ‘working.’ ”

H. Jack West, MD, agreed, adding that “in an ambiguous situation, a U.S.-based population is going to err on the side of overtreatment.”

Without “incontrovertible evidence” that immunotherapy should stop at 2 years, “many, many, many patients and clinicians are going to favor continuing ‘doing what you’re doing’ in the absence of either prohibitive toxicity or clinically significant disease progression,” said Dr. West of the City of Hope Comprehensive Cancer Center, Duarte, Calif.

One factor adding to this ambiguity: Most pivotal studies that examine first-line immunotherapy in NSCLC limit therapy duration to 2 years.

Another key factor is the absence of prospective data as to when to stop treatment for these patients, according to Martin Reck, MD, PhD, head of thoracic oncology at the Lung Clinic Grosshansdorf (Germany).

“We have never prospectively investigated the correlation of the duration of a checkpoint blockade and the efficacy of treatment,” Dr. Reck said. “And this is a big problem.” It means “we really do not know how long we should treat the patient.”

To make matters muddier, some data do suggest that more therapy may be better. The recent Checkmate 153 trial, for instance, found that patients who had no signs of disease progression and who received 1-year fixed-duration nivolumab had significantly shorter progression-free and overall survival than those who received treatment indefinitely.

However, randomized trials with longer-term follow-up suggest durable responses can be maintained for years after immunotherapy is stopped.

Data from the KEYNOTE-024 trial, for instance, showed that more than 45% of patients with metastatic NSCLC and high tumor PD-L1 expression who received pembrolizumab for 2 years remained alive at 5 years without further treatment or disease progression. Another trial, KEYNOTE-407, demonstrated similar 5-year survival outcomes among patients with advanced squamous NSCLC, regardless of PD-L1 status, who completed 2 years of chemotherapy plus pembrolizumab followed by maintenance pembrolizumab.

With these studies, however, “we can only speculate about whether the proportion of patients alive without progression would be substantially higher if treatment with immunotherapy continued longer,” Dr. West wrote in a recent editorial .

Perhaps the most telling data so far come from a recent retrospective analysis from Dr. Sun and colleagues. The researchers directly compared survival outcomes among patients who continued receiving immunotherapy indefinitely with outcomes among patients for whom immunotherapy was discontinued at 2 years.

The JAMA Oncology study, which focused on 706 patients with NSCLC who completed 2 years of therapy, found that only 16% stopped receiving immune checkpoint inhibitor therapy at 2 years, whereas the remaining 84% continued receiving treatment indefinitely.

Among patients who continued receiving immunotherapy for 2 additional years, overall survival was not better than among those who stopped receiving immunotherapy at the 2-year mark. Even among the 11 patients whose condition progressed when therapy was discontinued, most still did well after treatment was resumed.

However, the retrospective design of the study limits its impact.

Without more definitive “data about when the treatment can be stopped,” many continue “indefinitely as long as the patient is tolerating treatment and the disease is not progressing,” Conor E. Steuer, MD, and Suresh S. Ramalingam, MD, of Winship Cancer Institute at Emory University, Atlanta, wrote in a recent review.
 

Impact on practice?

Dr. Sun views her team’s findings not as a recommendation to halt immunotherapy for every patient at 2 years but rather as “one piece of data that may provide reassurance to providers and patients who wish to stop at 2 years.”

Ultimately, however, the decision as to when or whether to stop immunotherapy for long-term responders is “an individualized one that requires shared decision-making and consideration of each patient’s clinical history, preferences, and risk tolerance,” Dr. Sun explained.

Dr. Reck agreed, noting that until prospective trials evaluate a fixed approach, the duration of immunotherapy “has to be determined by the treating physician and the individual patient.”

For a patient with metastatic NSCLC who is having an excellent response to checkpoint blockade, “we are somewhat afraid to stop the immunotherapy,” explained Dr. Reck, “because we are afraid the disease might relapse.” However, he noted, for patients who have a stable response to therapy, it may make sense to consider discontinuing checkpoint blockade.

Outside of survival outcomes, oncologists should also consider quality of life. Stopping treatment at 2 years comes with a “lower risk of toxic effects, less time in treatment for patients, and considerably lower costs for our health care system,” said Dr. West.

But for a fixed strategy to become more standard practice, the burden of proof is high, Dr. West said.

Jonathan W. Goldman, MD, says he understands the mentality, “If it’s going well, why would I change?”

In his experience, at 2 years of immunotherapy, most patients “say they’re feeling great” and “don’t mind coming in every 4 or 6 weeks, depending on the drug,” said Dr. Goldman, director of clinical trials in thoracic oncology at UCLA Medical Center in Santa Monica, Calif.

Dr. Goldman noted that in the future, instead of continuing immunotherapy indefinitely, clinicians may aim to maintain the patient “in the best response possible,” adding an intervention, such as stereotactic body radiotherapy or radiologic ablation, when needed.

“It may be that many of these long-term disease control patients are not cured in a traditional sense,” Dr. Goldman said, “but have controlled cancer that could potentially last years or even decades with ongoing care.”

Dr. Sun has relationships with Regeneron, GenMab, Seagen, and Bayer and has received institutional funding from Blueprint Research, Seagen Research, and IO Biotech Research. Dr. West has relationships with AstraZeneca, Genentech/Roche, Merck, and Regeneron outside the submitted work. Dr. Reck has relationships with Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Lilly, Merck, MSD, Mirati, Novartis, Roche Regeneron, and Pfizer.

A version of this article appeared on Medscape.com.