Mixed Topics

You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.

Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.

“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.

“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.

She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”

Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”

The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”

The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.

“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.

She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”

That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”

She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
 

On the same page?

Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.

“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.

Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”

The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.

Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.

“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.

But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?

Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.

“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”

Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.

“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”

And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
 

Are “nonbinding” LOIs really not binding?

Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “

But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”

Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “

Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.

What to do before signing

So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”

He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.

Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”

At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.

That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.

“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”

At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.

The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.

Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”

She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
 

Negotiation tips

Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”

You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “

When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.

She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”

Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”

Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”

Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.

“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
 

A version of this article appeared on Medscape.com.

You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.

Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.

“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.

“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.

She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”

Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”

The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”

The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.

“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.

She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”

That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”

She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
 

On the same page?

Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.

“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.

Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”

The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.

Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.

“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.

But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?

Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.

“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”

Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.

“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”

And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
 

Are “nonbinding” LOIs really not binding?

Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “

But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”

Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “

Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.

What to do before signing

So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”

He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.

Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”

At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.

That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.

“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”

At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.

The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.

Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”

She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
 

Negotiation tips

Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”

You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “

When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.

She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”

Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”

Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”

Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.

“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
 

A version of this article appeared on Medscape.com.

You’ve just received an offer letter from that job you interviewed for. Sometimes you want to let the employer know right away how interested you are. The verbiage says the letter isn’t “binding.” So you eagerly sign on the dotted line. Everything looks great ... until it isn’t.

Attorney Ericka Adler, JD, LLM, a partner at Roetzel & Andress, a Chicago-based law firm that represents physicians and health care professionals nationwide, described her client who was in this predicament. The physician, a dermatologist, left a practice where she had been employed because she had received an “amazing” offer letter that included promises about her new work location, staffing, equipment, and hours. She signed and immediately gave notice to her previous employer.

“When she received the actual employment contract, none of those details from the offer letter – which is also called a letter of intent [LOI] – were included,” Ms. Adler told this news organization. The physician wanted to have the details from the LOI formally spelled out in the contract, but the employer refused.

“Basically, they said, ‘This is our standard contract and you’ll just have to trust us that we’ll keep our word. We meant what we said in the LOI, but we cannot include those details in the actual agreement because everyone has the same form of agreement.’ “ The physician decided to sign the contract and accept the position.

She contacted Ms. Adler after she had been at her new position for a month. “She had received none of the things they had promised her in the LOI,” Ms. Adler reported. “She lacked the NP and PA support, she lacked the equipment, she didn’t have enough exam rooms. As soon as she started, someone with whom she was sharing call coverage left, and she was expected to take over. The LOI had a cap on the amount of call she would be required to take, but that verbiage didn’t make it into the contract.”

Ms. Adler tried to address this issue with the employer. “We couldn’t say they had literally breached the agreement, but we did list the things that were mentioned in the LOI but on which they hadn’t delivered. We asked them to fix the issue within 10 days.”

The employer argued “that they didn’t have to fulfill anything that wasn’t spelled out in the contract, even if it was in the LOI. In fact, the contract specified clearly that the signed employment agreement was the only agreement and replaced any previous written or oral agreements between the parties.”

The dermatologist ultimately left the new position. “She might have been able to have a legal claim against the employer for breach or perhaps ‘detrimental reliance’ – meaning, she might have argued that she had been financially harmed due to the false promises made to her. But it would have been difficult and expensive for her to litigate the issue,” said Ms. Adler.

“It also didn’t seem like the physician could remain in the job and develop a positive work relationship with the employer, given that she felt betrayed and misled, and didn’t like the terms of employment, which didn’t match her needs or expectations,” said Ms. Adler.

She added that “most employers are not as unscrupulous and dishonest as this one was. But some employers do play on the fact that younger doctors – especially residents and fellows – tend to be trusting or feel they don’t have negotiation power. They’re often excited to get an offer and sign it without a second thought.”

That’s why she advises physicians to “review the terms of the LOI carefully and make sure you’re comfortable with them before signing it; but know that the real contract to negotiate will be the actual Employment Agreement.”

She also advises physicians not to give notice at their current place of employment until they’ve signed the final contract with the new employer.
 

On the same page?

Anu Murthy, JD, an attorney and associate contract review specialist at Contract Diagnostics, explained that the LOI is a document that the candidate receives after an interview but before a full contract. Sometimes, the LOI is preceded by a verbal or e-mailed offer, which is less formal.

“An LOI is sometimes called a Term Sheet or Memorandum of Understanding,“ Ms. Murthy told this news organization. “Typically, it lays out key provisions, such as compensation, initial term of the contract, location, and recruitment incentives.” Sometimes it includes mention of staffing, call schedule, malpractice, noncompete covenants, and other components of the position.

Justin Nabity, founder and CEO of Physicians Thrive, a physician financial advisory group, said that LOIs are “a way for employers to gauge a prospective employee’s level of interest.”

The employer “doesn’t want to send a contract with a lot of details before determining whether the candidate is really serious about the position, so the offer letter doesn’t show the whole picture,” Mr. Nabity told this news organization.

Dennis Hursh, managing partner of Physician Agreements Health Law, a Pennsylvania-based law firm that represents physicians, agreed.

“Another way of putting it is that the employer wants to see whether the prospective employee is on the same page. The LOI will typically include some key components that will later appear in a more complete and formal contract, together with other topics and details. Agreeing to those key components signals that indeed you and the employer are in accord,” said Mr. Hursh.

But are you really on the same page with your prospective employer? And if you seem to be on the same page, and you sign the LOI, is that a guarantee that the employer will honor its terms?

Not necessarily, according to the experts. In fact, many LOIs contain some verbiage stating that the letter isn’t binding, which can be confusing. Others suggest that it is binding, but the candidate doesn’t realize that the letter isn’t a formal contract and that the contract may contain details not included in the LOI or may omit details mentioned in the LOI, as happened to Ms. Adler’s unfortunate client.

“One of the pitfalls I see is that doctors sign the LOI without recognizing whether it’s binding or nonbinding,” Ms. Murthy said. “If it’s binding, it creates a legal obligation on your part and could preclude you from further negotiation once you see the contract and feel you’d like to negotiate some of its terms.”

Binding letters are typically offered to candidates after some back-and-forth between the parties, and important terms have been agreed to, which can happen either verbally or via e-mail. Once these agreements have been reached, they’re summarized in a “binding” letter before being extended into a full contract.

“But even if you’ve agreed on the terms verbally, it’s still important to have someone more experienced review the offer letter before signing it,” Ms. Murthy said. “It’s important to understand the ‘legalese’ and what your rights and obligations are before agreeing to anything.”

And certainly, if you receive a binding LOI, you shouldn’t sign anything until you’re sure you’re comfortable with its contents and have more details.
 

Are “nonbinding” LOIs really not binding?

Even if the LOI is nonbinding, that doesn’t necessarily mean you can sign it and expect to negotiate later. “I see people tripped up when they sign the LOI, thinking they’ll negotiate later,” said Mr. Hursh. “They may not like the terms – for example, they think the compensation is too low – and they figure they’ll work it out at the contract stage, because the LOI is ‘not legally binding.’ “

But because the candidate signed the LOI, “the employer is under the impression that the compensation was acceptable, so now you’ve tied your hands – and the hands of any attorney you may consult down the road – to negotiate those terms.”

Mr. Hursh said he is often consulted by physicians who signed the contract “to get the ball rolling,” thinking that the LOI was “just a meaningless bureaucratic paper.” They need to understand “that the employer wants to make sure they’re in agreement on the basic points before getting into the details,” he said. “Large hospitals with in-house counsel may not want to use their legal department’s valuable time in redrafting terms they thought were acceptable to the candidate, and most practices don’t want to pay a lawyer to draft an LOI and then come back and say, ‘Actually, the physician wants more compensation.’ “

Mr. Nabity summarized: “The LOI is essentially a negotiation tactic to take some of the cards out of the hands of the doctor and commit him or her to something they’re not ready to commit to.” Employers may be playing on the sense of pressure and candidate’s fear that the job will slip through their fingers if they wait too long to sign. “But it’s better to wait longer at this stage before signing even a nonbinding LOI,” he said.

What to do before signing

So how should physicians relate to the LOI? Mr. Nabity advises “working through the details of the offer letter first, going through it carefully and identifying areas of concern, bearing in mind that employers never begin with their best offer.”

He pointed out that physicians “rarely know their value and usually don’t know how to work through the dynamics of compensation, call schedules, additional incentives, bonuses, and productivity,” so they need to be informed about these areas before signing anything.

Ms. Murthy recommended “going back and saying [to the prospective employer], ‘Thank you, but I need time to consider and evaluate this offer.’ Then, do some due diligence.”

At that point, you can hire an attorney to go over the offer, educate yourself about compensation benchmarks and what your worth actually is, or consult another trained professional or more experienced individual who can review the LOI before you sign it.

That’s what Dominique Cleveland, MD, a Texas-based ob.gyn., did when she received an LOI 5 years ago.

“The offer letter from the group practice contained a statement that the group wanted me to come on board, what the salary would be, and the time frame that would be covered in the contract,” she told this news organization. “It mentioned benefits and incentives and relocation, but it was only a short document – maybe one or two pages long.”

At the time that she received her LOI, Dr. Cleveland was completing her residency. She consulted experienced faculty members from her institution to find out whether the terms laid out in the LOI “were the norm and were reasonable.” She was “fairly certain” that the salary was low and this was confirmed by the faculty members she talked to. “So I felt comfortable asking for more [compensation],” she said.

The employer was receptive to her proposed changes, which were included in the more detailed contract that followed. “I can’t say there were any surprises per se in the contract because I had negotiated my salary after receiving the offer letter,” she said. She accepted the position and has been working there ever since.

Dr. Cleveland advises physicians “not to make a decision without speaking to someone who’s experienced and can help you compare what’s out there.”

She also encourages physicians to ask for what they want, whether it’s compensation or something else, such as call schedule or vacation time, without being afraid. “I’m a firm believer that you won’t know what you can get if you don’t ask for it,” she said.
 

Negotiation tips

Mr. Nabity recommended not agreeing to any terms until you are ready to enter into negotiation, recognizing that negotiation is an “art” that requires skill and training. “Either get trained in negotiation, perhaps taking courses to advocate for yourself – which is rare, and most doctors aren’t likely to do this – or go to a trained advocate, such as a lawyer, who can do so on your behalf.”

You might share your concerns with the person who interviewed you, with the person whose name is on the LOI, or with the recruiter who can advocate on your behalf, Ms. Murthy said. “You can reach out to the recruiter and say, ‘I really appreciate the opportunity, but there are some things in the offer letter I’d like to continue discussing.’ “

When you’re ready to negotiate, be sure to assemble all of your “asks” in a single document rather than going back to the prospective employer with “multiple individual questions multiple times,” Ms. Murthy advised. It’s more efficient and the employer or recruiter will appreciate that.

She also advised couching your request in language that expresses your appreciation for the offer and stating that you would like the agreement to serve the best interests of both parties. “Use open-ended language like that, and ask if it’s all right for you to send back some questions, ask for clarification, or share concerns.”

Most employers “will be fine with that,” Ms. Murthy said. “Most won’t say, ‘This is it, take it or leave it.’ If they do, that’s a red flag for you to reconsider whether you really want to work for this particular employer.”

Mr. Hursh suggested that if you choose to sign the LOI immediately, so as to rapidly let the prospective employer know of your interest, “you should add some type of qualification such as, ‘I’m signing this to express my interest, but accepting the position will be dependent upon a more thorough review of compensation benchmarks,’ for example.”

Mr. Nabity agreed: “You can add a handwritten note to the signed LOI expressing that you’re eager to move forward and proceed with the position, but it shouldn’t be construed as accepting the terms of the LOI until you’ve seen the full contract.

“Remember, health care can’t exist without doctors,” Mr. Nabity said. “Doctors are the star players and should go into the negotiation process recognizing their true worth.”
 

A version of this article appeared on Medscape.com.

Adam Boggon, MBChB, was working at the Royal Free Hospital in North London during the city’s second wave of COVID-19. “I was effectively living in the hospital,” he recalled. “It felt like I was going 10,000 miles per hour, trying to corral hundreds of medical students and doctors.”

During a national lockdown, there were few places Dr. Boggon could escape to, but the Hampstead Heath swimming ponds mostly remained open. He swam there regularly to exercise and recharge even in winter.

“Swimming in cold water takes you out of yourself,” Dr. Boggon said. “It was such a release for someone who grew up in a rural place and had access to green space, even though the water is murky.” It also hovers around 50 °F (10 °C).

Jumping into cold water, well, kind of stinks. So why do it? It’s not only for bragging rights. A growing number of studies suggest significant mental and physical health benefits to swimming in cold water, specifically to improve depression symptoms and even ease inflammatory conditions.

And a lot of that research is driven by medical pros who love to do it themselves.

For Dr. Boggon, swimming in frigid water is uncomfortable, but he feels that a sensation of calmness follows that makes the plunge more than worth it. Now a Fulbright Scholar at Harvard, where he studies public health and health management, Dr. Boggon is able to frequent the fabled Walden Pond just outside of Boston.

As Thoreau himself said, “You can never have enough of nature.”

Yes, even if it’s really, really cold.
 

Taking a deeper dive

Heather Massey, PhD, a senior lecturer in Sport, Health, and Exercise Science at University of Portsmouth, blames her father, a dinghy sailor, for her affinity for cold-water swimming.

And she’s done more than most, including an epic 16-hour crossing of the English Channel. The water temperature was in the upper-50s °F, and she swam without a wetsuit. “Time just seemed to collapse,” she has shared about the experience.

While working on her PhD and studying the effects of environmental physiology, in particular what happens to the body when it gets hot or cold, Dr. Massey’s hobby and studies seemed to coalesce.

Her research initially focused on the hazards around being in cold open water. But she also noticed a growing trend of people claiming health benefits from the practice. “People started to talk about experiencing improved symptoms of depression or improved mental health from their activities in the water,” she said.

She partnered with another outdoor swimming enthusiast, Hannah Denton, a counseling psychologist working for the National Health Service in the United Kingdom. Ms. Denton was publishing papers on the potential impact that outdoor swimming may have on people with depression and how it could improve mental health in general. She also regularly engages in cold-water swims to boost feelings of mindfulness and peace.

“Having the experience of being so close to nature, as well as the strong sensory experience of being in cold water, does really encourage you to be in the moment,” Ms. Denton wrote in an article for the Sussex Mindfulness Centre. “My experiences of sea swimming and mindfulness support each other. Both have made me feel more comfortable with my body, to have more of a present moment focus, to pay attention to my breathing, and to gain distance from difficult thoughts.”

Over the past few years, Dr. Massey and Ms. Denton have moved from fairly small-scale studies with no real controls to today, completing a randomized controlled trial and looking at the impact that outdoor swimming may have on people living with mild to moderate depression.

“At first, people sort of thought our idea was a bit wacky,” said Dr. Massey. “Now, the popularity of open-water swimming has really blossomed, and so has this area of research. We’re starting to build more rigor into the work.”

Like all the researchers and physicians interviewed for this article, Dr. Massey hesitates to claim that cold-water swimming is a “cure” that should be medicalized.

“It’s not about prescribing it or forcing people to do it,” said Dr. Massey. “This is not something that a doctor should write on a prescription and say you should go and have eight 1-hour sessions of swimming.”
 

(Not yet) a common cure

Enter into the conversation Mark Harper, MD, PhD, consultant anesthetist at Sussex University Hospitals in the United Kingdom and Kristiansand, Norway. Dr. Harper is the author of the 2022 book, Chill: The Cold Water Swim Cure – A Transformative Guide to Renew Your Body and Mind.

Dr. Harper grew up swimming in pools, and it wasn’t until his pool closed for 2 weeks that he ventured into the sea. He recalled walking up the beach afterward, thinking, God, this feels good, and from that moment on, he became hooked on outdoor swimming and curious about its therapeutic potential.

The “cure” in the book’s title, Dr. Harper explained, is being used in the historical sense of “treatment,” as in the first medical book about sea-bathing written over 250 years ago. Dr. Harper acknowledged that the connection to health is still speculative. “However, the circumstantial evidence, the feedback from participants and early study data for its benefits are now very strong,” he said.

In a small study published in 2022, Dr. Harper and colleagues took 59 people with anxiety and depression and put them through a sea-swimming course. Afterward, 80% showed a clinically significant improvement in their mental health.

More recently, Dr. Harper and his team of researchers released a survey to determine how many people were using cold-water swimming as a treatment for a mental or physical ailment. “We thought 30 or 40 people would respond, but we ended up with over 700,” he said. “The majority were using it for mental health but also included inflammation-related conditions.”

Over 2 decades, Dr. Harper has seen dramatic success stories. In his book, he recalled a good friend who, in his early 20s, suffered from Crohn’s disease so badly he couldn’t walk up the steps to his parents’ house. The friend turned to outdoor cold swimming as a low-impact workout and began noticing the symptoms of his disease were improving. Within months, he was able to go off his medications. In 2022, he completed 52 triathlons: one per week for the entire year.
 

How cold exposure may play with your brain

Vaibhav Diwadkar, PhD, professor of psychiatry and behavioral neurosciences at Wayne State University, in Detroit, is studying how human brain networks respond to cold exposure. Dr. Diwadkar and his colleague, Otto Muzik, PhD, began by putting volunteers in a rubber suit with thin tubing and infusing the tubing with temperature-controlled water. Meanwhile, they collected functional brain imaging data to analyze which parts of the brain were responding as body temperature changed.

The data showed that the cold exposure made certain areas of the brain very active, including some that have been associated with the regulation of mood.

Dr. Diwadkar posits that controlled exposure to cold serves as a low-level stressor that knocks different systems within the brain and body out of homeostasis. Once the stress is removed, the brain responds by releasing neurotransmitters that enhance mood, frequently leading to feelings of euphoria in participants.

“We don’t have direct evidence of such a mechanism, but it’s a reasonable speculation,” said Dr. Diwadkar.

However, he pointed out that science writers in the media often portray topics such as this one in black and white, which is “oversimplifying the scientific complexity of biology.”

Clearly, more research needs to be done on the potential therapeutic benefits of cold-water swimming. But for those suffering from anxiety, depression, or chronic illness, if taking a cold dip makes you feel better, the why and how might be beside the point.

Plus, as Dr. Harper pointed out, it’s an easy and accessible therapy.

“All you need is some water – enough to submerge your entire body in – that’s less than 68 °F (20 °C),” he said. “If you stay long enough to get over that initial shock, which is just 2 or 3 minutes, then you’ve got the effect. If you get out and want to go back in again, then you’ve done it right.”
 

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

Adam Boggon, MBChB, was working at the Royal Free Hospital in North London during the city’s second wave of COVID-19. “I was effectively living in the hospital,” he recalled. “It felt like I was going 10,000 miles per hour, trying to corral hundreds of medical students and doctors.”

During a national lockdown, there were few places Dr. Boggon could escape to, but the Hampstead Heath swimming ponds mostly remained open. He swam there regularly to exercise and recharge even in winter.

“Swimming in cold water takes you out of yourself,” Dr. Boggon said. “It was such a release for someone who grew up in a rural place and had access to green space, even though the water is murky.” It also hovers around 50 °F (10 °C).

Jumping into cold water, well, kind of stinks. So why do it? It’s not only for bragging rights. A growing number of studies suggest significant mental and physical health benefits to swimming in cold water, specifically to improve depression symptoms and even ease inflammatory conditions.

And a lot of that research is driven by medical pros who love to do it themselves.

For Dr. Boggon, swimming in frigid water is uncomfortable, but he feels that a sensation of calmness follows that makes the plunge more than worth it. Now a Fulbright Scholar at Harvard, where he studies public health and health management, Dr. Boggon is able to frequent the fabled Walden Pond just outside of Boston.

As Thoreau himself said, “You can never have enough of nature.”

Yes, even if it’s really, really cold.
 

Taking a deeper dive

Heather Massey, PhD, a senior lecturer in Sport, Health, and Exercise Science at University of Portsmouth, blames her father, a dinghy sailor, for her affinity for cold-water swimming.

And she’s done more than most, including an epic 16-hour crossing of the English Channel. The water temperature was in the upper-50s °F, and she swam without a wetsuit. “Time just seemed to collapse,” she has shared about the experience.

While working on her PhD and studying the effects of environmental physiology, in particular what happens to the body when it gets hot or cold, Dr. Massey’s hobby and studies seemed to coalesce.

Her research initially focused on the hazards around being in cold open water. But she also noticed a growing trend of people claiming health benefits from the practice. “People started to talk about experiencing improved symptoms of depression or improved mental health from their activities in the water,” she said.

She partnered with another outdoor swimming enthusiast, Hannah Denton, a counseling psychologist working for the National Health Service in the United Kingdom. Ms. Denton was publishing papers on the potential impact that outdoor swimming may have on people with depression and how it could improve mental health in general. She also regularly engages in cold-water swims to boost feelings of mindfulness and peace.

“Having the experience of being so close to nature, as well as the strong sensory experience of being in cold water, does really encourage you to be in the moment,” Ms. Denton wrote in an article for the Sussex Mindfulness Centre. “My experiences of sea swimming and mindfulness support each other. Both have made me feel more comfortable with my body, to have more of a present moment focus, to pay attention to my breathing, and to gain distance from difficult thoughts.”

Over the past few years, Dr. Massey and Ms. Denton have moved from fairly small-scale studies with no real controls to today, completing a randomized controlled trial and looking at the impact that outdoor swimming may have on people living with mild to moderate depression.

“At first, people sort of thought our idea was a bit wacky,” said Dr. Massey. “Now, the popularity of open-water swimming has really blossomed, and so has this area of research. We’re starting to build more rigor into the work.”

Like all the researchers and physicians interviewed for this article, Dr. Massey hesitates to claim that cold-water swimming is a “cure” that should be medicalized.

“It’s not about prescribing it or forcing people to do it,” said Dr. Massey. “This is not something that a doctor should write on a prescription and say you should go and have eight 1-hour sessions of swimming.”
 

(Not yet) a common cure

Enter into the conversation Mark Harper, MD, PhD, consultant anesthetist at Sussex University Hospitals in the United Kingdom and Kristiansand, Norway. Dr. Harper is the author of the 2022 book, Chill: The Cold Water Swim Cure – A Transformative Guide to Renew Your Body and Mind.

Dr. Harper grew up swimming in pools, and it wasn’t until his pool closed for 2 weeks that he ventured into the sea. He recalled walking up the beach afterward, thinking, God, this feels good, and from that moment on, he became hooked on outdoor swimming and curious about its therapeutic potential.

The “cure” in the book’s title, Dr. Harper explained, is being used in the historical sense of “treatment,” as in the first medical book about sea-bathing written over 250 years ago. Dr. Harper acknowledged that the connection to health is still speculative. “However, the circumstantial evidence, the feedback from participants and early study data for its benefits are now very strong,” he said.

In a small study published in 2022, Dr. Harper and colleagues took 59 people with anxiety and depression and put them through a sea-swimming course. Afterward, 80% showed a clinically significant improvement in their mental health.

More recently, Dr. Harper and his team of researchers released a survey to determine how many people were using cold-water swimming as a treatment for a mental or physical ailment. “We thought 30 or 40 people would respond, but we ended up with over 700,” he said. “The majority were using it for mental health but also included inflammation-related conditions.”

Over 2 decades, Dr. Harper has seen dramatic success stories. In his book, he recalled a good friend who, in his early 20s, suffered from Crohn’s disease so badly he couldn’t walk up the steps to his parents’ house. The friend turned to outdoor cold swimming as a low-impact workout and began noticing the symptoms of his disease were improving. Within months, he was able to go off his medications. In 2022, he completed 52 triathlons: one per week for the entire year.
 

How cold exposure may play with your brain

Vaibhav Diwadkar, PhD, professor of psychiatry and behavioral neurosciences at Wayne State University, in Detroit, is studying how human brain networks respond to cold exposure. Dr. Diwadkar and his colleague, Otto Muzik, PhD, began by putting volunteers in a rubber suit with thin tubing and infusing the tubing with temperature-controlled water. Meanwhile, they collected functional brain imaging data to analyze which parts of the brain were responding as body temperature changed.

The data showed that the cold exposure made certain areas of the brain very active, including some that have been associated with the regulation of mood.

Dr. Diwadkar posits that controlled exposure to cold serves as a low-level stressor that knocks different systems within the brain and body out of homeostasis. Once the stress is removed, the brain responds by releasing neurotransmitters that enhance mood, frequently leading to feelings of euphoria in participants.

“We don’t have direct evidence of such a mechanism, but it’s a reasonable speculation,” said Dr. Diwadkar.

However, he pointed out that science writers in the media often portray topics such as this one in black and white, which is “oversimplifying the scientific complexity of biology.”

Clearly, more research needs to be done on the potential therapeutic benefits of cold-water swimming. But for those suffering from anxiety, depression, or chronic illness, if taking a cold dip makes you feel better, the why and how might be beside the point.

Plus, as Dr. Harper pointed out, it’s an easy and accessible therapy.

“All you need is some water – enough to submerge your entire body in – that’s less than 68 °F (20 °C),” he said. “If you stay long enough to get over that initial shock, which is just 2 or 3 minutes, then you’ve got the effect. If you get out and want to go back in again, then you’ve done it right.”
 

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

Adam Boggon, MBChB, was working at the Royal Free Hospital in North London during the city’s second wave of COVID-19. “I was effectively living in the hospital,” he recalled. “It felt like I was going 10,000 miles per hour, trying to corral hundreds of medical students and doctors.”

During a national lockdown, there were few places Dr. Boggon could escape to, but the Hampstead Heath swimming ponds mostly remained open. He swam there regularly to exercise and recharge even in winter.

“Swimming in cold water takes you out of yourself,” Dr. Boggon said. “It was such a release for someone who grew up in a rural place and had access to green space, even though the water is murky.” It also hovers around 50 °F (10 °C).

Jumping into cold water, well, kind of stinks. So why do it? It’s not only for bragging rights. A growing number of studies suggest significant mental and physical health benefits to swimming in cold water, specifically to improve depression symptoms and even ease inflammatory conditions.

And a lot of that research is driven by medical pros who love to do it themselves.

For Dr. Boggon, swimming in frigid water is uncomfortable, but he feels that a sensation of calmness follows that makes the plunge more than worth it. Now a Fulbright Scholar at Harvard, where he studies public health and health management, Dr. Boggon is able to frequent the fabled Walden Pond just outside of Boston.

As Thoreau himself said, “You can never have enough of nature.”

Yes, even if it’s really, really cold.
 

Taking a deeper dive

Heather Massey, PhD, a senior lecturer in Sport, Health, and Exercise Science at University of Portsmouth, blames her father, a dinghy sailor, for her affinity for cold-water swimming.

And she’s done more than most, including an epic 16-hour crossing of the English Channel. The water temperature was in the upper-50s °F, and she swam without a wetsuit. “Time just seemed to collapse,” she has shared about the experience.

While working on her PhD and studying the effects of environmental physiology, in particular what happens to the body when it gets hot or cold, Dr. Massey’s hobby and studies seemed to coalesce.

Her research initially focused on the hazards around being in cold open water. But she also noticed a growing trend of people claiming health benefits from the practice. “People started to talk about experiencing improved symptoms of depression or improved mental health from their activities in the water,” she said.

She partnered with another outdoor swimming enthusiast, Hannah Denton, a counseling psychologist working for the National Health Service in the United Kingdom. Ms. Denton was publishing papers on the potential impact that outdoor swimming may have on people with depression and how it could improve mental health in general. She also regularly engages in cold-water swims to boost feelings of mindfulness and peace.

“Having the experience of being so close to nature, as well as the strong sensory experience of being in cold water, does really encourage you to be in the moment,” Ms. Denton wrote in an article for the Sussex Mindfulness Centre. “My experiences of sea swimming and mindfulness support each other. Both have made me feel more comfortable with my body, to have more of a present moment focus, to pay attention to my breathing, and to gain distance from difficult thoughts.”

Over the past few years, Dr. Massey and Ms. Denton have moved from fairly small-scale studies with no real controls to today, completing a randomized controlled trial and looking at the impact that outdoor swimming may have on people living with mild to moderate depression.

“At first, people sort of thought our idea was a bit wacky,” said Dr. Massey. “Now, the popularity of open-water swimming has really blossomed, and so has this area of research. We’re starting to build more rigor into the work.”

Like all the researchers and physicians interviewed for this article, Dr. Massey hesitates to claim that cold-water swimming is a “cure” that should be medicalized.

“It’s not about prescribing it or forcing people to do it,” said Dr. Massey. “This is not something that a doctor should write on a prescription and say you should go and have eight 1-hour sessions of swimming.”
 

(Not yet) a common cure

Enter into the conversation Mark Harper, MD, PhD, consultant anesthetist at Sussex University Hospitals in the United Kingdom and Kristiansand, Norway. Dr. Harper is the author of the 2022 book, Chill: The Cold Water Swim Cure – A Transformative Guide to Renew Your Body and Mind.

Dr. Harper grew up swimming in pools, and it wasn’t until his pool closed for 2 weeks that he ventured into the sea. He recalled walking up the beach afterward, thinking, God, this feels good, and from that moment on, he became hooked on outdoor swimming and curious about its therapeutic potential.

The “cure” in the book’s title, Dr. Harper explained, is being used in the historical sense of “treatment,” as in the first medical book about sea-bathing written over 250 years ago. Dr. Harper acknowledged that the connection to health is still speculative. “However, the circumstantial evidence, the feedback from participants and early study data for its benefits are now very strong,” he said.

In a small study published in 2022, Dr. Harper and colleagues took 59 people with anxiety and depression and put them through a sea-swimming course. Afterward, 80% showed a clinically significant improvement in their mental health.

More recently, Dr. Harper and his team of researchers released a survey to determine how many people were using cold-water swimming as a treatment for a mental or physical ailment. “We thought 30 or 40 people would respond, but we ended up with over 700,” he said. “The majority were using it for mental health but also included inflammation-related conditions.”

Over 2 decades, Dr. Harper has seen dramatic success stories. In his book, he recalled a good friend who, in his early 20s, suffered from Crohn’s disease so badly he couldn’t walk up the steps to his parents’ house. The friend turned to outdoor cold swimming as a low-impact workout and began noticing the symptoms of his disease were improving. Within months, he was able to go off his medications. In 2022, he completed 52 triathlons: one per week for the entire year.
 

How cold exposure may play with your brain

Vaibhav Diwadkar, PhD, professor of psychiatry and behavioral neurosciences at Wayne State University, in Detroit, is studying how human brain networks respond to cold exposure. Dr. Diwadkar and his colleague, Otto Muzik, PhD, began by putting volunteers in a rubber suit with thin tubing and infusing the tubing with temperature-controlled water. Meanwhile, they collected functional brain imaging data to analyze which parts of the brain were responding as body temperature changed.

The data showed that the cold exposure made certain areas of the brain very active, including some that have been associated with the regulation of mood.

Dr. Diwadkar posits that controlled exposure to cold serves as a low-level stressor that knocks different systems within the brain and body out of homeostasis. Once the stress is removed, the brain responds by releasing neurotransmitters that enhance mood, frequently leading to feelings of euphoria in participants.

“We don’t have direct evidence of such a mechanism, but it’s a reasonable speculation,” said Dr. Diwadkar.

However, he pointed out that science writers in the media often portray topics such as this one in black and white, which is “oversimplifying the scientific complexity of biology.”

Clearly, more research needs to be done on the potential therapeutic benefits of cold-water swimming. But for those suffering from anxiety, depression, or chronic illness, if taking a cold dip makes you feel better, the why and how might be beside the point.

Plus, as Dr. Harper pointed out, it’s an easy and accessible therapy.

“All you need is some water – enough to submerge your entire body in – that’s less than 68 °F (20 °C),” he said. “If you stay long enough to get over that initial shock, which is just 2 or 3 minutes, then you’ve got the effect. If you get out and want to go back in again, then you’ve done it right.”
 

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

I was running my 25th New York City Marathon. It was 2018, and I almost pulled out of running that year. I wasn’t myself, and maybe that’s an understatement.

A month earlier, I had been involved in a malpractice case. I was found liable for $10 million. My colleagues didn’t think I had done anything wrong, but the jury did. And the local newspapers made me look like a villain.

I was devastated. But my priest, my friends, and my family all told me, “You can’t quit.” So, I decided to run for them.

I started on the Verrazzano-Narrows Bridge that morning with some friends from work. I usually listen to music as I’m running, but I didn’t that year. I was just in my zone, enjoying the crowds. They’re huge. Millions of people on the streets.

I was running well. I did half the race in an hour and 57 minutes. My family always meets me at mile 17, and I was almost there. I had reached 59th Street and was about to make the turn onto First Avenue.

That’s one of the noisiest places in the marathon. There’s a kind of tunnel, and with the crowd and the throng of runners, it’s incredibly loud. But somehow, I heard somebody yell, “Help!”

Now, how I heard that, I don’t know. And if I’d been listening to music like I always do, no way I would’ve heard it. I could swear it was an angel on my shoulder that said, “Turn around, dummy. You’ve got a person that needs your help to your left.”

I turned around and about 30 feet behind me, I saw a woman waving her hands and a runner on the ground. I thought, Somebody fainted. I pushed through the crowd to get to them. The woman was crying, saying, “My friend went down to tie her shoe and she fell back. I think she’s seizing or something.”

I got down and tried to wake the other woman up. I lifted her legs up. But I quickly realized there was more to the story. I felt for pulses and couldn’t feel them. I screamed for a defibrillator and started to do CPR.

Some volunteers and police started coming toward us. The police officers looked at me like, What’s this guy doing? I explained that I was a physician, and one of them began helping me with the CPR. As we did that, someone brought a defibrillator.

Meanwhile, runners were going past, almost over us. The police officers were trying to create a barrier.

The machine gave the woman a shock, but we didn’t get a response, so we resumed CPR. At that point, my legs began to cramp so badly I couldn’t go on. So the police officer took over, and I yelled, “I need an ambu bag!” Somebody brought one, and I started giving her oxygen.

At that point, a paramedic team arrived with a bigger defibrillator. We shocked her again. And again. That time we got results, but she quickly went out again. The fourth time, we got her heart back and she started breathing on her own.

We finally got her into an ambulance. I wanted to go with them, but the woman’s friend needed to get in, so there wasn’t enough room.

And then they were gone, and I was just standing there.

A police officer put his arm around me. He said, “Doc, you’re amazing. What do you need? Where can I take you?”

I said, “Take me? My wife is waiting for me at mile 17.”

I took off and ran. When I got to my wife and kids, they were so worried. We all wear tracking devices, and they could see that I had stopped for more than 20 minutes.

I fell into my wife’s arms and told her what had happened. I was crying. “I don’t know what to do. I need to get to the hospital.”

And she said, “No, you need to go finish the race.”

So, I did. It was painful because of the cramps, but I was numb at that point. I was thinking about the woman the whole way. My time was 5 hours and 20 minutes.

As soon as I finished, I went to every police officer I could find, but nobody knew anything. Suddenly, I remembered my cousin. He had previously been the head of EMS for New York City. I called him. “Abdo, it’s Ted, you’ve got to do me a favor.”

“What?” he said. “Are you delirious from running the marathon?”

I told him what I needed. He called me back 5 minutes later and said, “Ted, what’d you do? Everybody wants to know who you are and where you are! The woman just went out again at New York Cornell. But they got her back, and they’re bringing her up to the cath lab.”

After every marathon that I run, we host a big party at our house. My family and friends and neighbors all celebrate while I’m dying on the couch. That night, my daughter told everyone the story of what happened.

But I was still not right. Still thinking about the malpractice suit.

Yes, I just did something great. But I’d recently been called the worst physician in the world. The distraction of the marathon was gone, and I was back to thinking, What am I going to do with my life? Who’s ever going to want to see me again? I’m a pariah.

Everybody said, “Ted, what happened a month ago isn’t you. What happened today was you.”

I told them to leave it alone, but my daughter and my neighbor started calling people anyway. The next day I got a call from the local newspaper. It was the same journalist who had written about me from the trial. I told him I didn’t want to talk. I was actually pretty nasty.

But my wife said, “Ted, what are you doing? That guy was trying to help you.” So, I called back and apologized.

“Dr. Strange, we knew that story wasn’t right,” he said. “We have to write this story.”

After the article came out, I started getting more calls from the media. Channel 7 News and CBS News did segments. The New York Knicks invited us to a game and presented me with a watch. It was incredible. But I was also really embarrassed by it.

People started calling me a hero. I’m not a hero. I just did what I’m supposed to do, what I’m trained to do. Shame on me if I don’t do that. Good guy and hopefully good physician, sure, but not a hero.

I also give credit to the City of New York Police Department, the FDNY, and the volunteers. Without them, I couldn’t have done what I did. It was a true team effort.

A few weeks later, the woman went home to Minnesota. She’ll never run a marathon again, but she’s still alive to this day. It turned out she had a single lesion called the “widow-maker” lesion. She was in perfect health and had just completed an ultramarathon a few months before; but she had a genetic predisposition. She still calls me every December to thank me for another Christmas.

There’s more.

One year after this whole thing, almost to the date, I got a call from my attorney. “The court just threw out the malpractice verdict,” he said. “You didn’t do anything wrong.”

I’m a man of faith. And I believe all this happened for a reason. Maybe God was sending me a message, and that’s why I heard a call for help on 59th Street in my 25th marathon among millions of people in a crowd.

I ran the marathon the next year. And when I got to that spot, I stopped and reflected. Nobody knew why I was standing there, but I knew. To this day, I could take you to that spot.

I turn 65 next July, and I plan to keep on running the race.
 

Dr. Strange is chair of medicine at Staten Island University Hospital, associate ambulatory physician executive of the Staten Island Region, and an internal medicine and geriatric medicine physician with Northwell Health.

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

I was running my 25th New York City Marathon. It was 2018, and I almost pulled out of running that year. I wasn’t myself, and maybe that’s an understatement.

A month earlier, I had been involved in a malpractice case. I was found liable for $10 million. My colleagues didn’t think I had done anything wrong, but the jury did. And the local newspapers made me look like a villain.

I was devastated. But my priest, my friends, and my family all told me, “You can’t quit.” So, I decided to run for them.

I started on the Verrazzano-Narrows Bridge that morning with some friends from work. I usually listen to music as I’m running, but I didn’t that year. I was just in my zone, enjoying the crowds. They’re huge. Millions of people on the streets.

I was running well. I did half the race in an hour and 57 minutes. My family always meets me at mile 17, and I was almost there. I had reached 59th Street and was about to make the turn onto First Avenue.

That’s one of the noisiest places in the marathon. There’s a kind of tunnel, and with the crowd and the throng of runners, it’s incredibly loud. But somehow, I heard somebody yell, “Help!”

Now, how I heard that, I don’t know. And if I’d been listening to music like I always do, no way I would’ve heard it. I could swear it was an angel on my shoulder that said, “Turn around, dummy. You’ve got a person that needs your help to your left.”

I turned around and about 30 feet behind me, I saw a woman waving her hands and a runner on the ground. I thought, Somebody fainted. I pushed through the crowd to get to them. The woman was crying, saying, “My friend went down to tie her shoe and she fell back. I think she’s seizing or something.”

I got down and tried to wake the other woman up. I lifted her legs up. But I quickly realized there was more to the story. I felt for pulses and couldn’t feel them. I screamed for a defibrillator and started to do CPR.

Some volunteers and police started coming toward us. The police officers looked at me like, What’s this guy doing? I explained that I was a physician, and one of them began helping me with the CPR. As we did that, someone brought a defibrillator.

Meanwhile, runners were going past, almost over us. The police officers were trying to create a barrier.

The machine gave the woman a shock, but we didn’t get a response, so we resumed CPR. At that point, my legs began to cramp so badly I couldn’t go on. So the police officer took over, and I yelled, “I need an ambu bag!” Somebody brought one, and I started giving her oxygen.

At that point, a paramedic team arrived with a bigger defibrillator. We shocked her again. And again. That time we got results, but she quickly went out again. The fourth time, we got her heart back and she started breathing on her own.

We finally got her into an ambulance. I wanted to go with them, but the woman’s friend needed to get in, so there wasn’t enough room.

And then they were gone, and I was just standing there.

A police officer put his arm around me. He said, “Doc, you’re amazing. What do you need? Where can I take you?”

I said, “Take me? My wife is waiting for me at mile 17.”

I took off and ran. When I got to my wife and kids, they were so worried. We all wear tracking devices, and they could see that I had stopped for more than 20 minutes.

I fell into my wife’s arms and told her what had happened. I was crying. “I don’t know what to do. I need to get to the hospital.”

And she said, “No, you need to go finish the race.”

So, I did. It was painful because of the cramps, but I was numb at that point. I was thinking about the woman the whole way. My time was 5 hours and 20 minutes.

As soon as I finished, I went to every police officer I could find, but nobody knew anything. Suddenly, I remembered my cousin. He had previously been the head of EMS for New York City. I called him. “Abdo, it’s Ted, you’ve got to do me a favor.”

“What?” he said. “Are you delirious from running the marathon?”

I told him what I needed. He called me back 5 minutes later and said, “Ted, what’d you do? Everybody wants to know who you are and where you are! The woman just went out again at New York Cornell. But they got her back, and they’re bringing her up to the cath lab.”

After every marathon that I run, we host a big party at our house. My family and friends and neighbors all celebrate while I’m dying on the couch. That night, my daughter told everyone the story of what happened.

But I was still not right. Still thinking about the malpractice suit.

Yes, I just did something great. But I’d recently been called the worst physician in the world. The distraction of the marathon was gone, and I was back to thinking, What am I going to do with my life? Who’s ever going to want to see me again? I’m a pariah.

Everybody said, “Ted, what happened a month ago isn’t you. What happened today was you.”

I told them to leave it alone, but my daughter and my neighbor started calling people anyway. The next day I got a call from the local newspaper. It was the same journalist who had written about me from the trial. I told him I didn’t want to talk. I was actually pretty nasty.

But my wife said, “Ted, what are you doing? That guy was trying to help you.” So, I called back and apologized.

“Dr. Strange, we knew that story wasn’t right,” he said. “We have to write this story.”

After the article came out, I started getting more calls from the media. Channel 7 News and CBS News did segments. The New York Knicks invited us to a game and presented me with a watch. It was incredible. But I was also really embarrassed by it.

People started calling me a hero. I’m not a hero. I just did what I’m supposed to do, what I’m trained to do. Shame on me if I don’t do that. Good guy and hopefully good physician, sure, but not a hero.

I also give credit to the City of New York Police Department, the FDNY, and the volunteers. Without them, I couldn’t have done what I did. It was a true team effort.

A few weeks later, the woman went home to Minnesota. She’ll never run a marathon again, but she’s still alive to this day. It turned out she had a single lesion called the “widow-maker” lesion. She was in perfect health and had just completed an ultramarathon a few months before; but she had a genetic predisposition. She still calls me every December to thank me for another Christmas.

There’s more.

One year after this whole thing, almost to the date, I got a call from my attorney. “The court just threw out the malpractice verdict,” he said. “You didn’t do anything wrong.”

I’m a man of faith. And I believe all this happened for a reason. Maybe God was sending me a message, and that’s why I heard a call for help on 59th Street in my 25th marathon among millions of people in a crowd.

I ran the marathon the next year. And when I got to that spot, I stopped and reflected. Nobody knew why I was standing there, but I knew. To this day, I could take you to that spot.

I turn 65 next July, and I plan to keep on running the race.
 

Dr. Strange is chair of medicine at Staten Island University Hospital, associate ambulatory physician executive of the Staten Island Region, and an internal medicine and geriatric medicine physician with Northwell Health.

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

I was running my 25th New York City Marathon. It was 2018, and I almost pulled out of running that year. I wasn’t myself, and maybe that’s an understatement.

A month earlier, I had been involved in a malpractice case. I was found liable for $10 million. My colleagues didn’t think I had done anything wrong, but the jury did. And the local newspapers made me look like a villain.

I was devastated. But my priest, my friends, and my family all told me, “You can’t quit.” So, I decided to run for them.

I started on the Verrazzano-Narrows Bridge that morning with some friends from work. I usually listen to music as I’m running, but I didn’t that year. I was just in my zone, enjoying the crowds. They’re huge. Millions of people on the streets.

I was running well. I did half the race in an hour and 57 minutes. My family always meets me at mile 17, and I was almost there. I had reached 59th Street and was about to make the turn onto First Avenue.

That’s one of the noisiest places in the marathon. There’s a kind of tunnel, and with the crowd and the throng of runners, it’s incredibly loud. But somehow, I heard somebody yell, “Help!”

Now, how I heard that, I don’t know. And if I’d been listening to music like I always do, no way I would’ve heard it. I could swear it was an angel on my shoulder that said, “Turn around, dummy. You’ve got a person that needs your help to your left.”

I turned around and about 30 feet behind me, I saw a woman waving her hands and a runner on the ground. I thought, Somebody fainted. I pushed through the crowd to get to them. The woman was crying, saying, “My friend went down to tie her shoe and she fell back. I think she’s seizing or something.”

I got down and tried to wake the other woman up. I lifted her legs up. But I quickly realized there was more to the story. I felt for pulses and couldn’t feel them. I screamed for a defibrillator and started to do CPR.

Some volunteers and police started coming toward us. The police officers looked at me like, What’s this guy doing? I explained that I was a physician, and one of them began helping me with the CPR. As we did that, someone brought a defibrillator.

Meanwhile, runners were going past, almost over us. The police officers were trying to create a barrier.

The machine gave the woman a shock, but we didn’t get a response, so we resumed CPR. At that point, my legs began to cramp so badly I couldn’t go on. So the police officer took over, and I yelled, “I need an ambu bag!” Somebody brought one, and I started giving her oxygen.

At that point, a paramedic team arrived with a bigger defibrillator. We shocked her again. And again. That time we got results, but she quickly went out again. The fourth time, we got her heart back and she started breathing on her own.

We finally got her into an ambulance. I wanted to go with them, but the woman’s friend needed to get in, so there wasn’t enough room.

And then they were gone, and I was just standing there.

A police officer put his arm around me. He said, “Doc, you’re amazing. What do you need? Where can I take you?”

I said, “Take me? My wife is waiting for me at mile 17.”

I took off and ran. When I got to my wife and kids, they were so worried. We all wear tracking devices, and they could see that I had stopped for more than 20 minutes.

I fell into my wife’s arms and told her what had happened. I was crying. “I don’t know what to do. I need to get to the hospital.”

And she said, “No, you need to go finish the race.”

So, I did. It was painful because of the cramps, but I was numb at that point. I was thinking about the woman the whole way. My time was 5 hours and 20 minutes.

As soon as I finished, I went to every police officer I could find, but nobody knew anything. Suddenly, I remembered my cousin. He had previously been the head of EMS for New York City. I called him. “Abdo, it’s Ted, you’ve got to do me a favor.”

“What?” he said. “Are you delirious from running the marathon?”

I told him what I needed. He called me back 5 minutes later and said, “Ted, what’d you do? Everybody wants to know who you are and where you are! The woman just went out again at New York Cornell. But they got her back, and they’re bringing her up to the cath lab.”

After every marathon that I run, we host a big party at our house. My family and friends and neighbors all celebrate while I’m dying on the couch. That night, my daughter told everyone the story of what happened.

But I was still not right. Still thinking about the malpractice suit.

Yes, I just did something great. But I’d recently been called the worst physician in the world. The distraction of the marathon was gone, and I was back to thinking, What am I going to do with my life? Who’s ever going to want to see me again? I’m a pariah.

Everybody said, “Ted, what happened a month ago isn’t you. What happened today was you.”

I told them to leave it alone, but my daughter and my neighbor started calling people anyway. The next day I got a call from the local newspaper. It was the same journalist who had written about me from the trial. I told him I didn’t want to talk. I was actually pretty nasty.

But my wife said, “Ted, what are you doing? That guy was trying to help you.” So, I called back and apologized.

“Dr. Strange, we knew that story wasn’t right,” he said. “We have to write this story.”

After the article came out, I started getting more calls from the media. Channel 7 News and CBS News did segments. The New York Knicks invited us to a game and presented me with a watch. It was incredible. But I was also really embarrassed by it.

People started calling me a hero. I’m not a hero. I just did what I’m supposed to do, what I’m trained to do. Shame on me if I don’t do that. Good guy and hopefully good physician, sure, but not a hero.

I also give credit to the City of New York Police Department, the FDNY, and the volunteers. Without them, I couldn’t have done what I did. It was a true team effort.

A few weeks later, the woman went home to Minnesota. She’ll never run a marathon again, but she’s still alive to this day. It turned out she had a single lesion called the “widow-maker” lesion. She was in perfect health and had just completed an ultramarathon a few months before; but she had a genetic predisposition. She still calls me every December to thank me for another Christmas.

There’s more.

One year after this whole thing, almost to the date, I got a call from my attorney. “The court just threw out the malpractice verdict,” he said. “You didn’t do anything wrong.”

I’m a man of faith. And I believe all this happened for a reason. Maybe God was sending me a message, and that’s why I heard a call for help on 59th Street in my 25th marathon among millions of people in a crowd.

I ran the marathon the next year. And when I got to that spot, I stopped and reflected. Nobody knew why I was standing there, but I knew. To this day, I could take you to that spot.

I turn 65 next July, and I plan to keep on running the race.
 

Dr. Strange is chair of medicine at Staten Island University Hospital, associate ambulatory physician executive of the Staten Island Region, and an internal medicine and geriatric medicine physician with Northwell Health.

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

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

U.S. government advisers expressed discomfort with Acrotech Biopharma’s 2030 target completion date for a study meant to prove the clinical benefits of two lymphoma drugs that the company has been selling for years.

At a Nov. 16 meeting, the Oncologic Drugs Advisory Committee of the Food and Drug Administration reviewed the reasons for delays in confirmatory trials for pralatrexate (Folotyn) and belinostat (Beleodaq), both now owned by East Windsor, N.J.–based Acrotech. The FDA granted accelerated approval for pralatrexate in 2009 and belinostat in 2014.

“The consensus of the advisory committee is that we have significant concerns about the very prolonged delay and getting these confirmatory studies underway,” said Andy Chen, MD, PhD, of Oregon Health & Science University, Portland, who served as acting ODAC chair for the meeting.

Corporate ownership changes were among the reasons Acrotech cited for the long delays in producing the confirmatory research on pralatrexate and belinostat. Allos Therapeutics won the FDA approval of pralatrexate in 2009. In 2012, Spectrum Pharmaceuticals acquired Acrotech. Spectrum won approval of belinostat in 2014. Acrotech acquired Spectrum in 2019.

The FDA didn’t ask ODAC to take votes on any questions at the meeting. Instead, the FDA sought its expert feedback about how to address the prolonged delays with pralatrexate and belinostat research and, in general, how to promote more timely completion of confirmatory trials for drugs cleared by accelerated approval.

Pralatrexate and belinostat are both used to treat relapsed or refractory peripheral T-cell lymphoma, a rare and aggressive disease affecting about 10,000-15,000 people annually in the United States.

Through the accelerated approval process, the FDA seeks to speed medicines to people with fatal and serious conditions based on promising signs in clinical testing.

The initial pralatrexate and belinostat were based on phase 2, single-arm, monotherapy studies, with about 109 evaluable patients in the key pralatrexate study and 120 evaluable patients in the belinostat study. As is common, these phase 2 tests used measurements of cancer progression, known as the overall response rate.

The FDA then expects companies to show through more extensive testing that medicines cleared with accelerated approvals can deliver significant benefits, such as extending lives. When there are delays in confirmatory trials, patients can be exposed to medicines, often with significant side effects, that are unlikely to benefit them.

For example, the FDA granted an accelerated approval in 2011 for romidepsin for this use for peripheral T-cell lymphoma, the same condition for which pralatrexate and belinostat are used. But in 2021, Bristol-Myers Squibb withdrew the approval for that use of romidepsin when a confirmatory trial failed to meet the primary efficacy endpoint of progression free survival.

At the meeting, Richard Pazdur, MD, who leads oncology medicine at the FDA, urged Acrotech to shorten the time needed to determine whether its medicines deliver significant benefits to patients and thus merit full approval, or whether they too may fall short.

“We’re really in a situation where patients are caught in the middle here,” Dr. Pazdur said. “I feel very bad for that situation and very bad for the patients that they don’t have this information.”
 

‘Dangerous precedent’

The FDA in recent years has stepped up its efforts to get companies to complete their required studies on drugs cleared by accelerated approvals. The FDA has granted a total of 187 accelerated approvals for cancer drugs. Many of these cover new uses of established drugs and others serve to allow the introduction of new medicines.

For more than half of these cases, 96 of 187, the FDA already has learned that it made the right call in allowing early access to medicines. Companies have presented study results that confirmed the benefit of drugs and thus been able to convert accelerated approvals to traditional approvals.

But 27 of the 187 oncology accelerated approvals have been withdrawn. In these cases, subsequent research failed to establish the expected benefits of these cancer drugs.

And in 95 cases, the FDA and companies are still waiting for the results of studies to confirm the expected benefit of drugs granted accelerated approvals. The FDA classifies these as ongoing accelerated approvals. About 85% of these ongoing approvals were granted in the past 5 years, in contrast to 14 years for pralatrexate and 9 for belinostat.

“It sets a dangerous precedent for the other sponsors and drug companies to have such outliers from the same company,” said ODAC member Toni K. Choueiri, MD, of Harvard Medical School and the Dana-Farber Cancer Institute, both in Boston.

The current agreement between the FDA and Acrotech focuses on a phase 3 trial, SPI-BEL-301 as the confirmatory study. Acrotech’s plan is to start with dose optimization studies in part 1 of the trial, with part 2 meant to see if its medicines provide a significant benefit as measured by progression-free survival.

The plan is to compare treatments. One group of patients would get belinostat plus a common cancer regimen known as CHOP, another group would get pralatrexate plus the COP cancer regimen, which is CHOP without doxorubicin, and a third group would get CHOP.

Acrotech’s current time line is for part 1, which began in October, to finish by December 2025. Then the part 2 timeline would run from 2026 to 2030, with interim progression-free survival possible by 2028.

ODAC member Ashley Rosko, MD, a hematologist from Ohio State University, Columbus, asked Acrotech what steps it will take to try to speed recruitment for the study.

“We are going to implement many strategies,” including what’s called digital amplification, replied Ashish Anvekar, president of Acrotech. This will help identify patients and channel them toward participating clinical sites.

Alexander A. Vinks, PhD, PharmD, who served as a temporary member of ODAC for the Nov. 16 meeting, said many clinicians will not be excited about enrolling patients in this kind of large, traditionally designed study.

Dr. Vinks, who is professor emeritus at Cincinnati Children’s Hospital Medical Center and University of Cincinnati, now works with consultant group NDA, a firm that advises companies on developing drugs.

Dr. Vinks advised Acrotech should try “to pin down what is most likely a smaller study that could be simpler, but still give robust, informative data.”

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ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

ILLUSTRATIVE CASE

A 72-year-old man with well-controlled hypertension and chronic obstructive pulmonary disease is scheduled for right total hip arthroplasty (THA) due to severe arthritis. He will be admitted to the hospital overnight, and his orthopedic surgeon anticipates 2 to 3 days of inpatient recovery time. In addition to medical management of the patient’s comorbid conditions, the surgeon asks if you have any insight regarding VTE prophylaxis for this patient. Specifically, do you think aspirin is equal to LMWH for VTE prophylaxis?

All adults undergoing major orthopedic surgery are considered to be at high risk for postoperative VTE development, with those having lower-limb procedures at highest risk.² Of the more than 2.2 million THAs and total knee arthroplasties (TKAs) performed in the United States between 2012 and 2020, 55% were primary TKAs and 39% primary THAs.³ The American College of Chest Physicians (ACCP) estimated a baseline 35-day risk for VTE of 4.3% in patients undergoing major orthopedic surgery.⁴ The highest VTE risk occurs during the first 7 to 14 days post surgery (1.8% for symptomatic deep vein thrombosis [DVT] and 1% for pulmonary embolism [PE]), with a slightly lower risk during the subsequent 15 to 35 days (1% for symptomatic DVT and 0.5% for PE).⁴

Aspirin’s low cost, availability, and ease of administration make it an attractive choice for VTE prevention in patients post THA and TKA surgery. The Pulmonary Embolism Prevention (PEP) trial evaluated 13,356 patients undergoing hip fracture repair and 4088 patients undergoing arthroplasty and found aspirin to be safe and effective in prevention of VTEs compared with placebo. The investigators concluded that “there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism.”⁵ The PEP study, along with others, led to the emergence of aspirin monotherapy for VTE prophylaxis.

Current guidelines for perioperative VTE prophylaxis are based on American Society of Hematology (ASH) and ACCP recommendations. For patients undergoing THA or TKA, ASH suggests using aspirin or anticoagulants for VTE prophylaxis; when anticoagulants are used, they suggest using a direct oral anticoagulant (DOAC) over LMWH.⁶ The ASH guidelines are conditional recommendations based on very low certainty of effects, and the ASH panel recognized the need for further investigation with large, high-quality clinical trials.

The ACCP guidelines are clearer in recommending VTE prophylaxis vs no prophylaxis for major orthopedic surgeries and recommend the use of LMWH over other agents, including aspirin, DOACs, warfarin, and intermittent pneumatic compression (IPC) devices.⁴

Although prophylaxis is widely recommended to mitigate the elevated risk for VTE among patients undergoing orthopedic surgery, aspirin as monotherapy remains controversial.⁷ Many orthopedic surgeons prescribe aspirin as a sole VTE prophylaxis agent; however, this practice is not well supported by data from large, well-conducted, randomized trials or inferiority trials.²

STUDY SUMMARY

Aspirin did not meet the noninferiority criterion for postoperative VTE

The CRISTAL trial compared the use of aspirin vs LMWH (enoxaparin) for VTE prophylaxis in patients ages 18 years or older undergoing primary THA or TKA for osteoarthritis.¹ This Australian study used a cluster-randomized, crossover, registry-nested, noninferiority trial design. Of note, in Australia, aspirin is formulated in 100-mg tablets, equivalent to the standard 81-mg low-dose tablet in the United States.

Continue to: Patients taking prescribed antiplatelet...

Patients taking prescribed antiplatelet medication for preexisting conditions (~20% of patients in each group) were allowed to continue antiplatelet therapy during the trial. Patients were excluded if they were receiving an anticoagulant prior to their procedure or had a medical contraindication to aspirin or enoxaparin.

Thirty-one hospital sites were randomly assigned a treatment protocol using either aspirin or enoxaparin. Once target patient enrollment was met with the initial assigned medication, the site switched to the second/other agent. This resulted in 5675 patients in the aspirin group and 4036 in the enoxaparin group enrolled between April 2019 and ­December 2020, with final follow-up in ­August 2021; of these, 259 in the aspirin group and 249 in the enoxaparin group were lost to follow-up, opted out, or died.

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior to aspirin for postoperative VTE prophylaxis.

The aspirin group was given 100 mg PO daily and the enoxaparin group was given 40 mg SC daily (20 mg daily for patients weighing < 50 kg or with an estimated glomerular filtration rate < 30 mL/min/1.73 m²) for 35 days after THA and 14 days after TKA. Both treatment groups received IPC calf devices intraoperatively and postoperatively, and mobilization was offered on postoperative Day 0 or 1.

The primary outcome—development of symptomatic VTE within 90 days of the procedure—occurred in 187 (3.5%) patients in the aspirin group and 69 (1.8%) patients in the enoxaparin group (estimated difference = 1.97%; 95% CI, 0.54%-3.41%). This did not meet the noninferiority criterion for aspirin, based on an estimated assumed rate of 2% and a noninferiority margin of 1%, and in fact was statistically superior for enoxaparin (P = .007). There were no significant differences between the 2 groups in major bleeding or death within 90 days.¹

WHAT’S NEW

Enoxaparin was significantly superior to aspirin for VTE prophylaxis

Although this study was designed as a noninferiority trial, analysis showed enoxaparin to be significantly superior for postoperative VTE prophylaxis compared with aspirin.

Continue to: CAVEATS

Study aspirin dosing differed from US standard

This study showed significantly lower rates of symptomatic VTE in the enoxaparin group compared with the aspirin group; however, the majority of this difference was driven by rates of below-the-knee DVTs, which are clinically less relevant.⁸ Also, this trial used a 100-mg aspirin formulation, which is not available in the United States.

CHALLENGES TO IMPLEMENTATION

Aspirin is far cheaper and administered orally

Aspirin is significantly cheaper than enoxaparin, costing about $0.13 per dose (~$4 for 30 tablets at the 81-mg dose) vs roughly $9 per 40 mg/0.4 mL dose for enoxaparin.⁹ However, a cost-effectiveness analysis may be useful to determine (for example) whether the higher cost of enoxaparin may be offset by fewer DVTs and other sequelae. Lastly, LMWH is an injection, which some patients may refuse.

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; [email protected]

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; [email protected]

THE CASE

A 51-year-old Japanese woman presented with fever, sore throat, and dyspnea of less than 1 day’s duration. Although she had developed general fatigue, palpitations, and tremors of the hands 2 months earlier, she had not sought medical care.

Her medical history included Graves disease, which had been diagnosed 13 years earlier. She reported that her only medication was methimazole 10 mg/d. She did not have any family history of endocrinopathies or hematologic diseases.

Physical examination revealed a body temperature of 99.7 °F; heart rate, 130 beats/min; blood pressure, 182/62 mm Hg; respiratory rate, 46 breaths/min; and oxygen saturation, 100% on room air. Pharyngeal erythema was seen. Lung sounds were clear. The patient had tremors in her hands, tenderness of the thyroid gland, and exophthalmos. No leg edema or jugular vein distension was seen.

Laboratory tests indicated hyperthyroidism, with a thyroid-stimulating hormone level < 0.01 µIU/mL (normal range, 0.5-5 µIU/mL); free T3 level, 4.87 pg/mL (normal range, 2.3-4.3 pg/mL); and free T4 level, 2.97 ng/dL (normal range, 0.9-1.7 ng/dL). The patient also had a white blood cell (WBC) count of 1020 cells/µL (normal range, 3500-9000 cells/µL) and neutrophil count of 5 cells/µL (normal range, 1500-6500 cells/µL).

Other blood cell counts were normal, and a chest x-ray did not reveal any abnormal findings. In addition, there was no evidence to suggest hematologic malignancies or congenital neutropenia.

THE DIAGNOSIS

Based on the patient’s low WBC and neutrophil counts, agranulocytosis due to antithyroid drug therapy was suspected; however, this diagnosis would be highly unusual in the context of a 13-year history of therapy. Further history taking revealed that, because of her lack of financial means, unstable living conditions, and lack of understanding of the necessity for medication adherence, the patient had not taken methimazole regularly until 2 months prior to presentation, when she started taking it because of worsening symptoms. She had hesitated to report her social and medication status due to embarrassment.

In consideration of these factors, a diagnosis of exacerbation of hyperthyroidism and agranulocytosis (due to methimazole restart and upper respiratory infection) was made.

Continue to: DISCUSSION

Agranulocytosis is a severe adverse event of antithyroid agents and requires prompt diagnosis and treatment. In a 26-year study at one clinic, it occurred in approximately 0.4% of patients taking antithyroid agents.¹ The possible mechanisms of agranulocytosis are the direct toxicity of drugs and immune-mediated responses.² Older age, female sex, and some HLA genotypes are reported to be associated with susceptibility to agranulocytosis.²

Although the development of agranulocytosis tends to be dose related, a small dose of antithyroid agent can sometimes cause the condition.^3,4 It usually occurs within the first 3 months of treatment initiation, but occasionally patients develop agranulocytosis after long-term therapy.⁵ Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.⁵

Treatment includes drug cessation, administration of broad-spectrum antibiotics if infection is suspected, and granulocyte-­colony stimulating factor (G-CSF) therapy.⁵

Our patient was hospitalized, and methimazole was stopped immediately. Administration of potassium iodide 50 mg/d and G-CSF was started. Meropenem 3 g/d also was administered for neutropenic fever.

The patient’s condition improved, and her WBC count increased to 1640 cells/µL on Day 8 and 10,890 cells/µL on Day 9. G-CSF was stopped on Day 12 and meropenem on Day 13. Bone marrow aspiration was not performed because of improvement in lab values and her overall condition. Although monitoring of WBC count during methimazole therapy is controversial,⁵ we decided to routinely monitor this patient due to the possibility of drug cross-reactivity.

Continue to: Despite repeated explanations...

Despite repeated explanations that it was dangerous for a patient who had developed agranulocytosis to take another antithyroid medication, the patient refused surgical treatment or radioiodine ablation because of her financial situation. (While all Japanese citizens are covered by a national health insurance program, patients ages 6 to 70 years are required to pay approximately 30% of medical and pharmaceutical costs.) On Day 21, potassium iodide was stopped, and propylthiouracil 300 mg/d was administered with careful follow-up. Agranulocytosis did not recur.

Immediate problem solved, but what about the future?

During her hospital stay, the medical team spoke with the patient many times, during which she expressed anxiety about her health conditions and the difficulties that she had experienced in her life. The clinicians acknowledged her concerns and assured the patient of their continuing commitment to her well-being even after discharge. The patient also was advised that she should take her medication as prescribed and that if she had a fever or sore throat, she should stop the medication and seek medical care as soon as possible. The patient accepted the medical team’s advice and expressed hope for the future.

Conversations about medication adherence. In 1 survey, about 60% of patients taking antithyroid drugs were unfamiliar with the symptoms of agranulocytosis.⁶ To deliver safe and effective treatment and detect conditions such as agranulocytosis at an early stage, clinicians must communicate clearly with patients who have hyperthyroidism, providing sufficient explanation and ensuring understanding on the patient’s part.

Interruption and subsequent resumption of the same antithyroid drug treatment also can be a risk factor for agranulocytosis, as in this case.

Patients may be reluctant to provide the details of medication adherence.⁷ Although it is common for patients to need services for socioeconomic issues,⁸ health care professionals sometimes fail to adequately discuss these issues with patients, especially if the patients are marginalized and/or have lower economic status.⁹ Cases such as ours underscore the importance of improving clinicians’ awareness and sensitivity to patients’ socioeconomic challenges.^10,11

Our patient received information about welfare and other government services from a medical social worker during her hospital stay. She also was informed that she could seek assistance from medical social workers in the future if needed.

Continue to: The patient was discharged...

The patient was discharged on Day 28. After discharge, she took propylthiouracil as prescribed (300 mg/d), and her Graves disease was well controlled. Outpatient follow-up visits were performed every 1 or 2 months. No adverse events of propylthiouracil were seen in the ensuing time.

THE TAKEAWAY

Patients with chronic conditions sometimes discontinue medications, and they may not talk about it with their medical team, especially if they have socioeconomic or other difficulties in their lives. Clinicians should consider medication nonadherence and its risk factors when patients with chronic conditions develop unexpected adverse events.

ACKNOWLEDGMENT
We thank Jane Charbonneau, DVM, from Edanz for doing an English-language review of a draft of this manuscript.

CORRESPONDENCE
Takuya Maejima, MD, Department of General Medicine and Primary Care, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576 Japan; [email protected]

More than 1.2 million Americans are living with HIV, and more than 30,000 new cases are diagnosed each year. While total incidence has declined since 2016, HIV remains a nationwide epidemic.¹

Medications that prevent HIV acquisition, termed preexposure prophylaxis (PrEP), are an important tool to initiate in the primary care setting to reduce HIV transmission. However, while there are an estimated 1.2 million people eligible for PrEP, only 36% have received PrEP prescriptions.² Several barriers that have impeded its widespread adoption include a lack of clinician knowledge and clinical resources for testing, high medication costs, and stigma around sexual health and intravenous (IV) drug use.

The value of PrEP

PrEP is chemoprophylaxis against the acquisition of HIV infection through the administration of an oral or injectable medication to people at risk for HIV. This practice began in the early 2000s, with the first oral regimen approved in 2012, and since has become an important tool in preventing HIV transmission.

When taken as prescribed, PrEP medications reduce the risk for acquiring HIV through sex by approximately 99% and can reduce the risk for acquiring HIV from injection drug use by approximately 74%.³ The US Preventive Services Task Force issued a Grade “A” recommendation to offer PrEP to people at high risk for HIV acquisition in June 2019 and reaffirmed it in a 2023 update.⁴

PrEP is notably distinct from postexposure prophylaxis (PEP), which is the administration of medication to prevent HIV infection after a possible exposure.

The available regimens

Regimens for PrEP include oral tablets or intramuscular (IM) injections.⁵ There are 3 PrEP regimens approved by the US Food and Drug Administration (FDA): tenofovir disoproxil fumarate/­emtricitabine (Truvada), tenofovir ­alafenamide/emtricitabine (Descovy), and cabotegravir (Apretude).

Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare.

Truvada is once-daily oral PrEP that was approved in 2012 and is now available in a generic formulation. Notable adverse effects of Truvada include a small negative impact on renal function and small reductions in bone mineral density; these have been noted in individual trials, but in meta-­analyses such differences were not found to be statistically significant.^6-8 The most common adverse effects of Truvada, experienced by up to 6% of patients, are gastrointestinal symptoms, fatigue, headache/dizziness, depression, and insomnia; most symptoms resolve within weeks.

Continue to: Descovy

Descovy is daily oral PrEP that was approved in 2019. Descovy is associated with increases in LDL and triglycerides but has less impact on renal and bone health.⁹ The most common adverse effect of Descovy, experienced by about 5% of patients, is diarrhea, followed by nausea.

Apretude was approved in 2021 and is a 600-mg IM injection given monthly for 2 months, then every 2 months (± 7 days). The advantages of Apretude are frequency and discreteness of dosing and the ability to use in patients with estimated creatinine clearance (eCrCl) > 15 mL/min. The most common adverse effects of Apretude are injection-site reactions, which occur in 30% to 80% of patients but are rarely significant enough to lead to discontinuation (< 2% of patients discontinue use due to injection-site reactions).¹⁰ 

Who should take PrEP?

The latest Centers for Disease Control and Prevention (CDC) guidelines recommend that all sexually active adults receive information about PrEP.⁵ Indications for PrEP are broad and summarized in the FIGURE.⁵

PrEP is indicated in patients who report sexual or injection drug use behaviors that place them at substantial ongoing risk for HIV exposure. Specific indications include patients with sexual partner(s) with unknown HIV status with whom they have inconsistent or no condom use, a history of bacterial sexually transmitted infection (STI) in the past 6 months, an HIV-positive sexual partner, or the sharing of injection drug equipment.

Hepatitis B infection is not a contraindication for PrEP use, but knowledge of infection status is essential. All current oral medications used for PrEP have activity against hepatitis B. Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare. Hepatitis B surface antigen should be tested at the time of PrEP initiation, although PrEP can begin while testing is in process.

Continue to: How to use PrEP

At PrEP initiation, acute or chronic HIV infection must be excluded with a documented negative HIV antigen/antibody test within 1 week of prescribing PrEP.⁵ The CDC guidelines provide an updated HIV testing algorithm (www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf, p 30-31, Figures 4a and 4b), which considers whether patients have received PrEP recently.

Patients with recent high-risk exposures or symptoms of acute HIV at the time of desired PrEP initiation should have an HIV-1 viral load checked with negative results before PrEP is prescribed. Additional criteria for PrEP include weight > 35 kg; screening for hepatitis B virus infection; screening for drug interactions; and drug-specific eCrCl cutoffs of > 60 mL/min for Truvada, > 30 mL/min for Descovy, and > 15 mL/min for Apretude.⁵

Studies regarding time to medication effectiveness are limited. Pharmacokinetic studies of Truvada demonstrate sufficient drug concentrations should be present in peripheral blood mononuclear cells and rectal tissue within 7 days of initiation of oral dosing and around 20 days in vaginal tissue.

Of note, while expedited partner therapy is used as a harm-reduction strategy to treat the sexual partners of patients diagnosed with certain STIs, PrEP is not recommended to be used in this way.

Ongoing monitoring with PrEP. Once oral PrEP is started, STI risk assessment and HIV testing via 4th generation antibody/antigen­ test should be completed at least every 3 months. PrEP oral prescription refills should be limited to 3 months. For patients receiving IM PrEP (Apretude), HIV testing via viral load and antibody/antigen testing should be done at the time of each injection (every 2 months).⁵

Continue to: With oral PrEP...

With oral PrEP, renal function should be checked every 6 months in patients older than 50 years or those with eCrCl < 90 mL/min at initiation. For patients younger than 50 years with no baseline renal dysfunction, the latest guidelines now recommend monitoring every 12 months instead of 6 months.⁵

For patients on Descovy, a lipid panel is recommended at PrEP initiation and every 12 months. Testing for other STIs can be considered on this schedule, based on clinical assessment. The TABLE⁵ summarizes recommended monitoring for patients taking oral PrEP.

Recommended follow-up provides an opportunity to have frequent contact with a potentially high-risk population, and PrEP should be one part of a comprehensive HIV prevention and risk reduction plan. Many patients at high risk for HIV acquisition may benefit from frequent follow-up to address screening, referral, and treatment of substance use disorders, mental health conditions, and chronic medical conditions (including hepatitis C infection) and provide ongoing preventive health care. 

Special uses of PrEP 

Same-day PrEP. Starting PrEP on the day of the initial appointment may be appropriate based on patient risk factors and barriers to care, such as a high risk for contracting HIV before the subsequent appointment for a prescription of PrEP or an inability to return to the clinic in a timely fashion due to transportation or work constraints, or clinician availability. For these patients, assuming there is a low concern for acute or chronic HIV infection, PrEP can be initiated on the day of the initial visit.⁵

In these cases, point-of-care HIV and creatinine testing with same-day results should be completed. Antigen/antibody fingerstick testing or HIV-1 RNA test are preferred; oral fluid HIV testing should not be used for same-day PrEP due to its lower sensitivity for HIV detection. If same-day testing is unavailable, blood should be drawn at the visit so that HIV and creatinine testing can be completed as soon as possible.

Continue to: In addition to initial laboratory testing...

In addition to initial laboratory testing, clinics offering same-day PrEP should be able to provide: (1) assistance for patients to enroll in health insurance or a medication assistance program (eg, Ready, Set, PrEP) for those ineligible for insurance coverage, (2) rapid follow-­up on all laboratory results with reliable patient contact information, and (3) follow-up appointments with clinicians able to prescribe and administer PrEP medications.

Off-label “on-demand” PrEP. An off-label treatment regimen for men who have sex with men (MSM) is termed “on-demand” PrEP or “2-1-1 PrEP” and is included in the CDC guidelines for consideration by clinicians.⁵ This alternative dosing schedule can be used for individuals who have sex less frequently and in a more planned fashion.

On-demand PrEP requires a patient to take 2 tablets of Truvada 2 to 24 hours before sex, followed by 1 tablet 24 hours and 1 tablet 48 hours after sexual activity. If a sexual act occurs at 48 hours, the patient should extend the daily dose for 48 additional hours, such that PrEP is always used daily for 48 hours after the last sex act.

This method has been studied with Truvada in MSM in Europe and Canada through the IPERGAY and PREVENIR trials and shown to have ≥ 86% efficacy in preventing HIV acquisition.^11,12 The only US-based study showed lower efficacy; however, based on the currently available data, the International Antiviral Society-USA Panel has recommended it as an alternative regimen.^13,14

PrEP via telehealth. Visits for PrEP initiation and continuation can be completed via telehealth.⁵ Patients then can complete necessary laboratory tests by going to a physical laboratory location or using mailed specimen kits in which they can self-collect urine, oral/rectal swabs, and fingerstick blood samples.

Continue to: PrEP use in specific populations

Adolescents

Truvada, Descovy, and Apretude all are now approved for use in adolescents weighing ≥ 35 kg. Two important considerations when prescribing to this population are the effects of Truvada on bone health and the unique barriers to access.

In studies of adolescent MSM using Truvada for PrEP, bone mineral density declined, especially among those ages 15 to 19 years.¹⁵ As such, the clinical impact of decreased bone mineral density should be weighed against the risk for HIV acquisition; however, bone mineral density monitoring is not recommended in the current guidelines. CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.⁵

Confidentiality and legal issues exist when prescribing PrEP to minors. In terms of parental/guardian involvement, clinicians who are prescribing PrEP for patients younger than 18 years should consult the CDC website for guidance on local and state regulations that govern prescribing and confidentiality (www.cdc.gov/hiv/policies/law/states/­minors.html).

CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.

Insurance billing statements may lead to inadvertent disclosure of a minor’s decision to take PrEP to their legal guardian.¹⁶ Generic Truvada costs less than $100 for a 3-month supply when using goodrx.com, which may offer an alternative to insurance for medication payment. 

Peripartum patients

The increased risk for HIV acquisition in the peripartum period for female patients is well documented.¹⁷ Guidelines recommend offering PrEP with Truvada to female patients at risk for conception, currently pregnant, or breastfeeding when that patient’s partner has HIV and the partner’s viral load is unknown or detectable. Descovy is not recommended for pregnant or breastfeeding patients.⁵ Cabotegravir­-containing regimens (Apretude) have not been approved by the FDA for pregnant or breastfeeding patients.⁵

Continue to: Data on the impact of...

Data on the impact of Truvada for PrEP on fetal health are still emerging. A large study in Kenya showed no significant differences in preterm birth, low birth weight, or early infant growth, and a randomized, noninferiority trial in South Africa showed no association between Truvada for PrEP and preterm birth or the birth of small-for-­gestational-age infants.^18,19 There are no definitive studies of breastfeeding infants exposed to Truvada, but data from previous trials of breastfeeding mothers who were taking the individual components that are combined in the Truvada pill indicated there is minimal medication exposure to the infant.⁵

PrEP studies in the peripartum period to date have been conducted exclusively among cisgender women, and data do not yet reflect the experiences of transgender men, genderqueer people, and nonbinary individuals in the peripartum period.⁵

Transgender people

Transgender women should be strongly considered candidates for PrEP as they are at an extremely high risk for HIV acquisition. The most recent National HIV Behavioral Surveillance survey found that approximately 42% of transgender women were living with HIV.²⁰ The survey revealed stark racial and ethnic disparities among transgender women living with HIV: 62% identified as Black/African American, compared with 35% Hispanic/Latina and 17% White.²⁰

Transgender women report high rates of sexual assault, unprotected receptive anal sex, commercial sex work, homelessness, mental health disorders, and substance use, putting them at increased risk for HIV acquisition.²¹ However, transgender women are less likely to have discussed PrEP with a clinician, are less likely to be on PrEP even when interested in starting, and have higher rates of medication nonadherence compared with cisgender MSM.^21,22 PrEP has not been found to decrease levels of feminizing hormones; however, studies are mixed as to whether feminizing hormones decrease Truvada concentrations in rectal mucosa, so clinicians should emphasize the importance of daily medication adherence.²³

Transgender men have not been included in any PrEP trials, so no specific recommendations are available. 

Continue to: Disparities in PrEP access and use exist

The lifetime risk for HIV acquisition is 9% among White MSM, 50% among Black MSM, and 20% among Hispanic MSM.²⁴ Despite this large disparity in disease burden, Black and Hispanic individuals are less likely to be aware of PrEP, have discussed PrEP with a health care professional, or used PrEP compared with their White counterparts.²⁵ As a result, in 2020, PrEP coverage for eligible White individuals was 61%, while coverage among eligible Black and Hispanic/Latino individuals was just 8% and 14%, respectively.²⁶

Rural areas have been shown to lag behind urban areas in PrEP awareness and use.

Surveillance data comparing male and female PrEP coverage reveal further disparities between the sexes, with PrEP coverage for eligible female-at-birth patients estimated to be 9% compared with 25.8% for male-at-birth patients.²⁶ The gap between the risk for HIV infection and the access to and uptake of PrEP coverage is most pronounced among Black women, for whom the rate of new HIV diagnosis is > 10 times higher than it is for White women, but who have some of the lowest awareness and utilization rates of all demographics.²⁷

The rural population at risk. Disparities in HIV awareness and PrEP use also exist between rural and urban populations, as well as by health insurance status. Rural areas have been shown to lag behind urban areas in PrEP awareness and use. Two potential explanations for this disparity are differences­ in HIV- and drug use–associated stigma and health insurance status. Greater stigma against drug use and HIV in rural areas has been associated with lower rates of PrEP use.²⁸

Individuals younger than 65 years in rural areas are less likely to have private health insurance and more likely to be uninsured compared with their urban counterparts, which may impact access to clinicians knowledgeable about PrEP.²⁹ Notably, MSM who live in states that have expanded Medicaid have higher rates of PrEP use compared with MSM living in states that have not expanded Medicaid.³⁰

Health insurers in the United States are required to cover PrEP medication, clinician visits, and associated blood work with no patient cost-sharing, although implementation barriers such as prior authorizations still exist. 

Conclusion

Family physicians are well positioned to identify patients at risk for HIV infection, prescribe PrEP, organize comprehensive follow-up care, and partner with their health systems and local communities to reduce barriers to care. Those who can leverage existing relationships with local health departments, school-based health clinics, congregate housing programs, LGBTQIA+ advocacy groups, harm-reduction coalitions, and other community-based organizations to raise PrEP awareness play a critical role in preventing HIV transmission and reducing health care disparities in their communities.

CORRESPONDENCE
Andrew V.A. Foley, MD, MPH, Erie Family Health Centers, 2418 W Division Street, Chicago, IL 60622; [email protected]

More than 1.2 million Americans are living with HIV, and more than 30,000 new cases are diagnosed each year. While total incidence has declined since 2016, HIV remains a nationwide epidemic.¹

Medications that prevent HIV acquisition, termed preexposure prophylaxis (PrEP), are an important tool to initiate in the primary care setting to reduce HIV transmission. However, while there are an estimated 1.2 million people eligible for PrEP, only 36% have received PrEP prescriptions.² Several barriers that have impeded its widespread adoption include a lack of clinician knowledge and clinical resources for testing, high medication costs, and stigma around sexual health and intravenous (IV) drug use.

The value of PrEP

PrEP is chemoprophylaxis against the acquisition of HIV infection through the administration of an oral or injectable medication to people at risk for HIV. This practice began in the early 2000s, with the first oral regimen approved in 2012, and since has become an important tool in preventing HIV transmission.

When taken as prescribed, PrEP medications reduce the risk for acquiring HIV through sex by approximately 99% and can reduce the risk for acquiring HIV from injection drug use by approximately 74%.³ The US Preventive Services Task Force issued a Grade “A” recommendation to offer PrEP to people at high risk for HIV acquisition in June 2019 and reaffirmed it in a 2023 update.⁴

PrEP is notably distinct from postexposure prophylaxis (PEP), which is the administration of medication to prevent HIV infection after a possible exposure.

The available regimens

Regimens for PrEP include oral tablets or intramuscular (IM) injections.⁵ There are 3 PrEP regimens approved by the US Food and Drug Administration (FDA): tenofovir disoproxil fumarate/­emtricitabine (Truvada), tenofovir ­alafenamide/emtricitabine (Descovy), and cabotegravir (Apretude).

Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare.

Truvada is once-daily oral PrEP that was approved in 2012 and is now available in a generic formulation. Notable adverse effects of Truvada include a small negative impact on renal function and small reductions in bone mineral density; these have been noted in individual trials, but in meta-­analyses such differences were not found to be statistically significant.^6-8 The most common adverse effects of Truvada, experienced by up to 6% of patients, are gastrointestinal symptoms, fatigue, headache/dizziness, depression, and insomnia; most symptoms resolve within weeks.

Continue to: Descovy

Descovy is daily oral PrEP that was approved in 2019. Descovy is associated with increases in LDL and triglycerides but has less impact on renal and bone health.⁹ The most common adverse effect of Descovy, experienced by about 5% of patients, is diarrhea, followed by nausea.

Apretude was approved in 2021 and is a 600-mg IM injection given monthly for 2 months, then every 2 months (± 7 days). The advantages of Apretude are frequency and discreteness of dosing and the ability to use in patients with estimated creatinine clearance (eCrCl) > 15 mL/min. The most common adverse effects of Apretude are injection-site reactions, which occur in 30% to 80% of patients but are rarely significant enough to lead to discontinuation (< 2% of patients discontinue use due to injection-site reactions).¹⁰ 

Who should take PrEP?

The latest Centers for Disease Control and Prevention (CDC) guidelines recommend that all sexually active adults receive information about PrEP.⁵ Indications for PrEP are broad and summarized in the FIGURE.⁵

PrEP is indicated in patients who report sexual or injection drug use behaviors that place them at substantial ongoing risk for HIV exposure. Specific indications include patients with sexual partner(s) with unknown HIV status with whom they have inconsistent or no condom use, a history of bacterial sexually transmitted infection (STI) in the past 6 months, an HIV-positive sexual partner, or the sharing of injection drug equipment.

Hepatitis B infection is not a contraindication for PrEP use, but knowledge of infection status is essential. All current oral medications used for PrEP have activity against hepatitis B. Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare. Hepatitis B surface antigen should be tested at the time of PrEP initiation, although PrEP can begin while testing is in process.

Continue to: How to use PrEP

At PrEP initiation, acute or chronic HIV infection must be excluded with a documented negative HIV antigen/antibody test within 1 week of prescribing PrEP.⁵ The CDC guidelines provide an updated HIV testing algorithm (www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf, p 30-31, Figures 4a and 4b), which considers whether patients have received PrEP recently.

Patients with recent high-risk exposures or symptoms of acute HIV at the time of desired PrEP initiation should have an HIV-1 viral load checked with negative results before PrEP is prescribed. Additional criteria for PrEP include weight > 35 kg; screening for hepatitis B virus infection; screening for drug interactions; and drug-specific eCrCl cutoffs of > 60 mL/min for Truvada, > 30 mL/min for Descovy, and > 15 mL/min for Apretude.⁵

Studies regarding time to medication effectiveness are limited. Pharmacokinetic studies of Truvada demonstrate sufficient drug concentrations should be present in peripheral blood mononuclear cells and rectal tissue within 7 days of initiation of oral dosing and around 20 days in vaginal tissue.

Of note, while expedited partner therapy is used as a harm-reduction strategy to treat the sexual partners of patients diagnosed with certain STIs, PrEP is not recommended to be used in this way.

Ongoing monitoring with PrEP. Once oral PrEP is started, STI risk assessment and HIV testing via 4th generation antibody/antigen­ test should be completed at least every 3 months. PrEP oral prescription refills should be limited to 3 months. For patients receiving IM PrEP (Apretude), HIV testing via viral load and antibody/antigen testing should be done at the time of each injection (every 2 months).⁵

Continue to: With oral PrEP...

With oral PrEP, renal function should be checked every 6 months in patients older than 50 years or those with eCrCl < 90 mL/min at initiation. For patients younger than 50 years with no baseline renal dysfunction, the latest guidelines now recommend monitoring every 12 months instead of 6 months.⁵

For patients on Descovy, a lipid panel is recommended at PrEP initiation and every 12 months. Testing for other STIs can be considered on this schedule, based on clinical assessment. The TABLE⁵ summarizes recommended monitoring for patients taking oral PrEP.

Recommended follow-up provides an opportunity to have frequent contact with a potentially high-risk population, and PrEP should be one part of a comprehensive HIV prevention and risk reduction plan. Many patients at high risk for HIV acquisition may benefit from frequent follow-up to address screening, referral, and treatment of substance use disorders, mental health conditions, and chronic medical conditions (including hepatitis C infection) and provide ongoing preventive health care. 

Special uses of PrEP 

Same-day PrEP. Starting PrEP on the day of the initial appointment may be appropriate based on patient risk factors and barriers to care, such as a high risk for contracting HIV before the subsequent appointment for a prescription of PrEP or an inability to return to the clinic in a timely fashion due to transportation or work constraints, or clinician availability. For these patients, assuming there is a low concern for acute or chronic HIV infection, PrEP can be initiated on the day of the initial visit.⁵

In these cases, point-of-care HIV and creatinine testing with same-day results should be completed. Antigen/antibody fingerstick testing or HIV-1 RNA test are preferred; oral fluid HIV testing should not be used for same-day PrEP due to its lower sensitivity for HIV detection. If same-day testing is unavailable, blood should be drawn at the visit so that HIV and creatinine testing can be completed as soon as possible.

Continue to: In addition to initial laboratory testing...

In addition to initial laboratory testing, clinics offering same-day PrEP should be able to provide: (1) assistance for patients to enroll in health insurance or a medication assistance program (eg, Ready, Set, PrEP) for those ineligible for insurance coverage, (2) rapid follow-­up on all laboratory results with reliable patient contact information, and (3) follow-up appointments with clinicians able to prescribe and administer PrEP medications.

Off-label “on-demand” PrEP. An off-label treatment regimen for men who have sex with men (MSM) is termed “on-demand” PrEP or “2-1-1 PrEP” and is included in the CDC guidelines for consideration by clinicians.⁵ This alternative dosing schedule can be used for individuals who have sex less frequently and in a more planned fashion.

On-demand PrEP requires a patient to take 2 tablets of Truvada 2 to 24 hours before sex, followed by 1 tablet 24 hours and 1 tablet 48 hours after sexual activity. If a sexual act occurs at 48 hours, the patient should extend the daily dose for 48 additional hours, such that PrEP is always used daily for 48 hours after the last sex act.

This method has been studied with Truvada in MSM in Europe and Canada through the IPERGAY and PREVENIR trials and shown to have ≥ 86% efficacy in preventing HIV acquisition.^11,12 The only US-based study showed lower efficacy; however, based on the currently available data, the International Antiviral Society-USA Panel has recommended it as an alternative regimen.^13,14

PrEP via telehealth. Visits for PrEP initiation and continuation can be completed via telehealth.⁵ Patients then can complete necessary laboratory tests by going to a physical laboratory location or using mailed specimen kits in which they can self-collect urine, oral/rectal swabs, and fingerstick blood samples.

Continue to: PrEP use in specific populations

Adolescents

Truvada, Descovy, and Apretude all are now approved for use in adolescents weighing ≥ 35 kg. Two important considerations when prescribing to this population are the effects of Truvada on bone health and the unique barriers to access.

In studies of adolescent MSM using Truvada for PrEP, bone mineral density declined, especially among those ages 15 to 19 years.¹⁵ As such, the clinical impact of decreased bone mineral density should be weighed against the risk for HIV acquisition; however, bone mineral density monitoring is not recommended in the current guidelines. CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.⁵

Confidentiality and legal issues exist when prescribing PrEP to minors. In terms of parental/guardian involvement, clinicians who are prescribing PrEP for patients younger than 18 years should consult the CDC website for guidance on local and state regulations that govern prescribing and confidentiality (www.cdc.gov/hiv/policies/law/states/­minors.html).

CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.

Insurance billing statements may lead to inadvertent disclosure of a minor’s decision to take PrEP to their legal guardian.¹⁶ Generic Truvada costs less than $100 for a 3-month supply when using goodrx.com, which may offer an alternative to insurance for medication payment. 

Peripartum patients

The increased risk for HIV acquisition in the peripartum period for female patients is well documented.¹⁷ Guidelines recommend offering PrEP with Truvada to female patients at risk for conception, currently pregnant, or breastfeeding when that patient’s partner has HIV and the partner’s viral load is unknown or detectable. Descovy is not recommended for pregnant or breastfeeding patients.⁵ Cabotegravir­-containing regimens (Apretude) have not been approved by the FDA for pregnant or breastfeeding patients.⁵

Continue to: Data on the impact of...

Data on the impact of Truvada for PrEP on fetal health are still emerging. A large study in Kenya showed no significant differences in preterm birth, low birth weight, or early infant growth, and a randomized, noninferiority trial in South Africa showed no association between Truvada for PrEP and preterm birth or the birth of small-for-­gestational-age infants.^18,19 There are no definitive studies of breastfeeding infants exposed to Truvada, but data from previous trials of breastfeeding mothers who were taking the individual components that are combined in the Truvada pill indicated there is minimal medication exposure to the infant.⁵

PrEP studies in the peripartum period to date have been conducted exclusively among cisgender women, and data do not yet reflect the experiences of transgender men, genderqueer people, and nonbinary individuals in the peripartum period.⁵

Transgender people

Transgender women should be strongly considered candidates for PrEP as they are at an extremely high risk for HIV acquisition. The most recent National HIV Behavioral Surveillance survey found that approximately 42% of transgender women were living with HIV.²⁰ The survey revealed stark racial and ethnic disparities among transgender women living with HIV: 62% identified as Black/African American, compared with 35% Hispanic/Latina and 17% White.²⁰

Transgender women report high rates of sexual assault, unprotected receptive anal sex, commercial sex work, homelessness, mental health disorders, and substance use, putting them at increased risk for HIV acquisition.²¹ However, transgender women are less likely to have discussed PrEP with a clinician, are less likely to be on PrEP even when interested in starting, and have higher rates of medication nonadherence compared with cisgender MSM.^21,22 PrEP has not been found to decrease levels of feminizing hormones; however, studies are mixed as to whether feminizing hormones decrease Truvada concentrations in rectal mucosa, so clinicians should emphasize the importance of daily medication adherence.²³

Transgender men have not been included in any PrEP trials, so no specific recommendations are available. 

Continue to: Disparities in PrEP access and use exist

The lifetime risk for HIV acquisition is 9% among White MSM, 50% among Black MSM, and 20% among Hispanic MSM.²⁴ Despite this large disparity in disease burden, Black and Hispanic individuals are less likely to be aware of PrEP, have discussed PrEP with a health care professional, or used PrEP compared with their White counterparts.²⁵ As a result, in 2020, PrEP coverage for eligible White individuals was 61%, while coverage among eligible Black and Hispanic/Latino individuals was just 8% and 14%, respectively.²⁶

Rural areas have been shown to lag behind urban areas in PrEP awareness and use.

Surveillance data comparing male and female PrEP coverage reveal further disparities between the sexes, with PrEP coverage for eligible female-at-birth patients estimated to be 9% compared with 25.8% for male-at-birth patients.²⁶ The gap between the risk for HIV infection and the access to and uptake of PrEP coverage is most pronounced among Black women, for whom the rate of new HIV diagnosis is > 10 times higher than it is for White women, but who have some of the lowest awareness and utilization rates of all demographics.²⁷

The rural population at risk. Disparities in HIV awareness and PrEP use also exist between rural and urban populations, as well as by health insurance status. Rural areas have been shown to lag behind urban areas in PrEP awareness and use. Two potential explanations for this disparity are differences­ in HIV- and drug use–associated stigma and health insurance status. Greater stigma against drug use and HIV in rural areas has been associated with lower rates of PrEP use.²⁸

Individuals younger than 65 years in rural areas are less likely to have private health insurance and more likely to be uninsured compared with their urban counterparts, which may impact access to clinicians knowledgeable about PrEP.²⁹ Notably, MSM who live in states that have expanded Medicaid have higher rates of PrEP use compared with MSM living in states that have not expanded Medicaid.³⁰

Health insurers in the United States are required to cover PrEP medication, clinician visits, and associated blood work with no patient cost-sharing, although implementation barriers such as prior authorizations still exist. 

Conclusion

Family physicians are well positioned to identify patients at risk for HIV infection, prescribe PrEP, organize comprehensive follow-up care, and partner with their health systems and local communities to reduce barriers to care. Those who can leverage existing relationships with local health departments, school-based health clinics, congregate housing programs, LGBTQIA+ advocacy groups, harm-reduction coalitions, and other community-based organizations to raise PrEP awareness play a critical role in preventing HIV transmission and reducing health care disparities in their communities.

CORRESPONDENCE
Andrew V.A. Foley, MD, MPH, Erie Family Health Centers, 2418 W Division Street, Chicago, IL 60622; [email protected]

More than 1.2 million Americans are living with HIV, and more than 30,000 new cases are diagnosed each year. While total incidence has declined since 2016, HIV remains a nationwide epidemic.¹

Medications that prevent HIV acquisition, termed preexposure prophylaxis (PrEP), are an important tool to initiate in the primary care setting to reduce HIV transmission. However, while there are an estimated 1.2 million people eligible for PrEP, only 36% have received PrEP prescriptions.² Several barriers that have impeded its widespread adoption include a lack of clinician knowledge and clinical resources for testing, high medication costs, and stigma around sexual health and intravenous (IV) drug use.

The value of PrEP

PrEP is chemoprophylaxis against the acquisition of HIV infection through the administration of an oral or injectable medication to people at risk for HIV. This practice began in the early 2000s, with the first oral regimen approved in 2012, and since has become an important tool in preventing HIV transmission.

When taken as prescribed, PrEP medications reduce the risk for acquiring HIV through sex by approximately 99% and can reduce the risk for acquiring HIV from injection drug use by approximately 74%.³ The US Preventive Services Task Force issued a Grade “A” recommendation to offer PrEP to people at high risk for HIV acquisition in June 2019 and reaffirmed it in a 2023 update.⁴

PrEP is notably distinct from postexposure prophylaxis (PEP), which is the administration of medication to prevent HIV infection after a possible exposure.

The available regimens

Regimens for PrEP include oral tablets or intramuscular (IM) injections.⁵ There are 3 PrEP regimens approved by the US Food and Drug Administration (FDA): tenofovir disoproxil fumarate/­emtricitabine (Truvada), tenofovir ­alafenamide/emtricitabine (Descovy), and cabotegravir (Apretude).

Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare.

Truvada is once-daily oral PrEP that was approved in 2012 and is now available in a generic formulation. Notable adverse effects of Truvada include a small negative impact on renal function and small reductions in bone mineral density; these have been noted in individual trials, but in meta-­analyses such differences were not found to be statistically significant.^6-8 The most common adverse effects of Truvada, experienced by up to 6% of patients, are gastrointestinal symptoms, fatigue, headache/dizziness, depression, and insomnia; most symptoms resolve within weeks.

Continue to: Descovy

Descovy is daily oral PrEP that was approved in 2019. Descovy is associated with increases in LDL and triglycerides but has less impact on renal and bone health.⁹ The most common adverse effect of Descovy, experienced by about 5% of patients, is diarrhea, followed by nausea.

Apretude was approved in 2021 and is a 600-mg IM injection given monthly for 2 months, then every 2 months (± 7 days). The advantages of Apretude are frequency and discreteness of dosing and the ability to use in patients with estimated creatinine clearance (eCrCl) > 15 mL/min. The most common adverse effects of Apretude are injection-site reactions, which occur in 30% to 80% of patients but are rarely significant enough to lead to discontinuation (< 2% of patients discontinue use due to injection-site reactions).¹⁰ 

Who should take PrEP?

The latest Centers for Disease Control and Prevention (CDC) guidelines recommend that all sexually active adults receive information about PrEP.⁵ Indications for PrEP are broad and summarized in the FIGURE.⁵

PrEP is indicated in patients who report sexual or injection drug use behaviors that place them at substantial ongoing risk for HIV exposure. Specific indications include patients with sexual partner(s) with unknown HIV status with whom they have inconsistent or no condom use, a history of bacterial sexually transmitted infection (STI) in the past 6 months, an HIV-positive sexual partner, or the sharing of injection drug equipment.

Hepatitis B infection is not a contraindication for PrEP use, but knowledge of infection status is essential. All current oral medications used for PrEP have activity against hepatitis B. Incomplete adherence to or abrupt discontinuation of oral PrEP could precipitate a hepatitis B flare. Hepatitis B surface antigen should be tested at the time of PrEP initiation, although PrEP can begin while testing is in process.

Continue to: How to use PrEP

At PrEP initiation, acute or chronic HIV infection must be excluded with a documented negative HIV antigen/antibody test within 1 week of prescribing PrEP.⁵ The CDC guidelines provide an updated HIV testing algorithm (www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf, p 30-31, Figures 4a and 4b), which considers whether patients have received PrEP recently.

Patients with recent high-risk exposures or symptoms of acute HIV at the time of desired PrEP initiation should have an HIV-1 viral load checked with negative results before PrEP is prescribed. Additional criteria for PrEP include weight > 35 kg; screening for hepatitis B virus infection; screening for drug interactions; and drug-specific eCrCl cutoffs of > 60 mL/min for Truvada, > 30 mL/min for Descovy, and > 15 mL/min for Apretude.⁵

Studies regarding time to medication effectiveness are limited. Pharmacokinetic studies of Truvada demonstrate sufficient drug concentrations should be present in peripheral blood mononuclear cells and rectal tissue within 7 days of initiation of oral dosing and around 20 days in vaginal tissue.

Of note, while expedited partner therapy is used as a harm-reduction strategy to treat the sexual partners of patients diagnosed with certain STIs, PrEP is not recommended to be used in this way.

Ongoing monitoring with PrEP. Once oral PrEP is started, STI risk assessment and HIV testing via 4th generation antibody/antigen­ test should be completed at least every 3 months. PrEP oral prescription refills should be limited to 3 months. For patients receiving IM PrEP (Apretude), HIV testing via viral load and antibody/antigen testing should be done at the time of each injection (every 2 months).⁵

Continue to: With oral PrEP...

With oral PrEP, renal function should be checked every 6 months in patients older than 50 years or those with eCrCl < 90 mL/min at initiation. For patients younger than 50 years with no baseline renal dysfunction, the latest guidelines now recommend monitoring every 12 months instead of 6 months.⁵

For patients on Descovy, a lipid panel is recommended at PrEP initiation and every 12 months. Testing for other STIs can be considered on this schedule, based on clinical assessment. The TABLE⁵ summarizes recommended monitoring for patients taking oral PrEP.

Recommended follow-up provides an opportunity to have frequent contact with a potentially high-risk population, and PrEP should be one part of a comprehensive HIV prevention and risk reduction plan. Many patients at high risk for HIV acquisition may benefit from frequent follow-up to address screening, referral, and treatment of substance use disorders, mental health conditions, and chronic medical conditions (including hepatitis C infection) and provide ongoing preventive health care. 

Special uses of PrEP 

Same-day PrEP. Starting PrEP on the day of the initial appointment may be appropriate based on patient risk factors and barriers to care, such as a high risk for contracting HIV before the subsequent appointment for a prescription of PrEP or an inability to return to the clinic in a timely fashion due to transportation or work constraints, or clinician availability. For these patients, assuming there is a low concern for acute or chronic HIV infection, PrEP can be initiated on the day of the initial visit.⁵

In these cases, point-of-care HIV and creatinine testing with same-day results should be completed. Antigen/antibody fingerstick testing or HIV-1 RNA test are preferred; oral fluid HIV testing should not be used for same-day PrEP due to its lower sensitivity for HIV detection. If same-day testing is unavailable, blood should be drawn at the visit so that HIV and creatinine testing can be completed as soon as possible.

Continue to: In addition to initial laboratory testing...

In addition to initial laboratory testing, clinics offering same-day PrEP should be able to provide: (1) assistance for patients to enroll in health insurance or a medication assistance program (eg, Ready, Set, PrEP) for those ineligible for insurance coverage, (2) rapid follow-­up on all laboratory results with reliable patient contact information, and (3) follow-up appointments with clinicians able to prescribe and administer PrEP medications.

Off-label “on-demand” PrEP. An off-label treatment regimen for men who have sex with men (MSM) is termed “on-demand” PrEP or “2-1-1 PrEP” and is included in the CDC guidelines for consideration by clinicians.⁵ This alternative dosing schedule can be used for individuals who have sex less frequently and in a more planned fashion.

On-demand PrEP requires a patient to take 2 tablets of Truvada 2 to 24 hours before sex, followed by 1 tablet 24 hours and 1 tablet 48 hours after sexual activity. If a sexual act occurs at 48 hours, the patient should extend the daily dose for 48 additional hours, such that PrEP is always used daily for 48 hours after the last sex act.

This method has been studied with Truvada in MSM in Europe and Canada through the IPERGAY and PREVENIR trials and shown to have ≥ 86% efficacy in preventing HIV acquisition.^11,12 The only US-based study showed lower efficacy; however, based on the currently available data, the International Antiviral Society-USA Panel has recommended it as an alternative regimen.^13,14

PrEP via telehealth. Visits for PrEP initiation and continuation can be completed via telehealth.⁵ Patients then can complete necessary laboratory tests by going to a physical laboratory location or using mailed specimen kits in which they can self-collect urine, oral/rectal swabs, and fingerstick blood samples.

Continue to: PrEP use in specific populations

Adolescents

Truvada, Descovy, and Apretude all are now approved for use in adolescents weighing ≥ 35 kg. Two important considerations when prescribing to this population are the effects of Truvada on bone health and the unique barriers to access.

In studies of adolescent MSM using Truvada for PrEP, bone mineral density declined, especially among those ages 15 to 19 years.¹⁵ As such, the clinical impact of decreased bone mineral density should be weighed against the risk for HIV acquisition; however, bone mineral density monitoring is not recommended in the current guidelines. CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.⁵

Confidentiality and legal issues exist when prescribing PrEP to minors. In terms of parental/guardian involvement, clinicians who are prescribing PrEP for patients younger than 18 years should consult the CDC website for guidance on local and state regulations that govern prescribing and confidentiality (www.cdc.gov/hiv/policies/law/states/­minors.html).

CDC guidelines suggest considering Descovy for male adolescents given its potential lower impact on bone mineral density.

Insurance billing statements may lead to inadvertent disclosure of a minor’s decision to take PrEP to their legal guardian.¹⁶ Generic Truvada costs less than $100 for a 3-month supply when using goodrx.com, which may offer an alternative to insurance for medication payment. 

Peripartum patients

The increased risk for HIV acquisition in the peripartum period for female patients is well documented.¹⁷ Guidelines recommend offering PrEP with Truvada to female patients at risk for conception, currently pregnant, or breastfeeding when that patient’s partner has HIV and the partner’s viral load is unknown or detectable. Descovy is not recommended for pregnant or breastfeeding patients.⁵ Cabotegravir­-containing regimens (Apretude) have not been approved by the FDA for pregnant or breastfeeding patients.⁵

Continue to: Data on the impact of...

Data on the impact of Truvada for PrEP on fetal health are still emerging. A large study in Kenya showed no significant differences in preterm birth, low birth weight, or early infant growth, and a randomized, noninferiority trial in South Africa showed no association between Truvada for PrEP and preterm birth or the birth of small-for-­gestational-age infants.^18,19 There are no definitive studies of breastfeeding infants exposed to Truvada, but data from previous trials of breastfeeding mothers who were taking the individual components that are combined in the Truvada pill indicated there is minimal medication exposure to the infant.⁵

PrEP studies in the peripartum period to date have been conducted exclusively among cisgender women, and data do not yet reflect the experiences of transgender men, genderqueer people, and nonbinary individuals in the peripartum period.⁵

Transgender people

Transgender women should be strongly considered candidates for PrEP as they are at an extremely high risk for HIV acquisition. The most recent National HIV Behavioral Surveillance survey found that approximately 42% of transgender women were living with HIV.²⁰ The survey revealed stark racial and ethnic disparities among transgender women living with HIV: 62% identified as Black/African American, compared with 35% Hispanic/Latina and 17% White.²⁰

Transgender women report high rates of sexual assault, unprotected receptive anal sex, commercial sex work, homelessness, mental health disorders, and substance use, putting them at increased risk for HIV acquisition.²¹ However, transgender women are less likely to have discussed PrEP with a clinician, are less likely to be on PrEP even when interested in starting, and have higher rates of medication nonadherence compared with cisgender MSM.^21,22 PrEP has not been found to decrease levels of feminizing hormones; however, studies are mixed as to whether feminizing hormones decrease Truvada concentrations in rectal mucosa, so clinicians should emphasize the importance of daily medication adherence.²³

Transgender men have not been included in any PrEP trials, so no specific recommendations are available. 

Continue to: Disparities in PrEP access and use exist

The lifetime risk for HIV acquisition is 9% among White MSM, 50% among Black MSM, and 20% among Hispanic MSM.²⁴ Despite this large disparity in disease burden, Black and Hispanic individuals are less likely to be aware of PrEP, have discussed PrEP with a health care professional, or used PrEP compared with their White counterparts.²⁵ As a result, in 2020, PrEP coverage for eligible White individuals was 61%, while coverage among eligible Black and Hispanic/Latino individuals was just 8% and 14%, respectively.²⁶

Rural areas have been shown to lag behind urban areas in PrEP awareness and use.

Surveillance data comparing male and female PrEP coverage reveal further disparities between the sexes, with PrEP coverage for eligible female-at-birth patients estimated to be 9% compared with 25.8% for male-at-birth patients.²⁶ The gap between the risk for HIV infection and the access to and uptake of PrEP coverage is most pronounced among Black women, for whom the rate of new HIV diagnosis is > 10 times higher than it is for White women, but who have some of the lowest awareness and utilization rates of all demographics.²⁷

The rural population at risk. Disparities in HIV awareness and PrEP use also exist between rural and urban populations, as well as by health insurance status. Rural areas have been shown to lag behind urban areas in PrEP awareness and use. Two potential explanations for this disparity are differences­ in HIV- and drug use–associated stigma and health insurance status. Greater stigma against drug use and HIV in rural areas has been associated with lower rates of PrEP use.²⁸

Individuals younger than 65 years in rural areas are less likely to have private health insurance and more likely to be uninsured compared with their urban counterparts, which may impact access to clinicians knowledgeable about PrEP.²⁹ Notably, MSM who live in states that have expanded Medicaid have higher rates of PrEP use compared with MSM living in states that have not expanded Medicaid.³⁰

Health insurers in the United States are required to cover PrEP medication, clinician visits, and associated blood work with no patient cost-sharing, although implementation barriers such as prior authorizations still exist. 

Conclusion

Family physicians are well positioned to identify patients at risk for HIV infection, prescribe PrEP, organize comprehensive follow-up care, and partner with their health systems and local communities to reduce barriers to care. Those who can leverage existing relationships with local health departments, school-based health clinics, congregate housing programs, LGBTQIA+ advocacy groups, harm-reduction coalitions, and other community-based organizations to raise PrEP awareness play a critical role in preventing HIV transmission and reducing health care disparities in their communities.

CORRESPONDENCE
Andrew V.A. Foley, MD, MPH, Erie Family Health Centers, 2418 W Division Street, Chicago, IL 60622; [email protected]

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

Every once in a while, medicine changes in a fundamental way, and we may not realize it while it’s happening. I wasn’t around in 1928 when Fleming discovered penicillin; or in 1953 when Watson, Crick, and Franklin characterized the double-helical structure of DNA.

But looking at medicine today, there are essentially two places where I think we will see, in retrospect, that we were at a fundamental turning point. One is artificial intelligence, which gets so much attention and hype that I will simply say yes, this will change things, stay tuned.

The other is a bit more obscure, but I suspect it may be just as impactful. That other thing is RNA therapeutics – the medicines of the future.

I want to start with the idea that many diseases are, fundamentally, a problem of proteins. In some cases, like hypercholesterolemia, the body produces too much protein; in others, like hemophilia, too little.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

JAMA

JAMA

JAMA

JAMA

The New England Journal of Medicine

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

Every once in a while, medicine changes in a fundamental way, and we may not realize it while it’s happening. I wasn’t around in 1928 when Fleming discovered penicillin; or in 1953 when Watson, Crick, and Franklin characterized the double-helical structure of DNA.

But looking at medicine today, there are essentially two places where I think we will see, in retrospect, that we were at a fundamental turning point. One is artificial intelligence, which gets so much attention and hype that I will simply say yes, this will change things, stay tuned.

The other is a bit more obscure, but I suspect it may be just as impactful. That other thing is RNA therapeutics – the medicines of the future.

I want to start with the idea that many diseases are, fundamentally, a problem of proteins. In some cases, like hypercholesterolemia, the body produces too much protein; in others, like hemophilia, too little.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

JAMA

JAMA

JAMA

JAMA

The New England Journal of Medicine

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

Every once in a while, medicine changes in a fundamental way, and we may not realize it while it’s happening. I wasn’t around in 1928 when Fleming discovered penicillin; or in 1953 when Watson, Crick, and Franklin characterized the double-helical structure of DNA.

But looking at medicine today, there are essentially two places where I think we will see, in retrospect, that we were at a fundamental turning point. One is artificial intelligence, which gets so much attention and hype that I will simply say yes, this will change things, stay tuned.

The other is a bit more obscure, but I suspect it may be just as impactful. That other thing is RNA therapeutics – the medicines of the future.

I want to start with the idea that many diseases are, fundamentally, a problem of proteins. In some cases, like hypercholesterolemia, the body produces too much protein; in others, like hemophilia, too little.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

JAMA

JAMA

JAMA

JAMA

The New England Journal of Medicine

Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.