Mixed Topics

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Robert Louis Stevenson famously said, “Wine is bottled poetry.” And I think it works quite well. I’ve had wines that are simple, elegant, and unpretentious like Emily Dickinson, and passionate and mysterious like Pablo Neruda. And I’ve had wines that are more analogous to the limerick you might read scrawled on a rest-stop bathroom wall. Those ones give me headaches.

Wine headaches are on my mind this week, not only because of the incoming tide of Beaujolais nouveau, but because of a new study which claims to have finally explained the link between wine consumption and headaches – and apparently it’s not just the alcohol.

Headaches are common, and headaches after drinking alcohol are particularly common. An interesting epidemiologic phenomenon, not yet adequately explained, is why red wine is associated with more headache than other forms of alcohol. There have been many studies fingering many suspects, from sulfites to tannins to various phenolic compounds, but none have really provided a concrete explanation for what might be going on.

A new hypothesis came to the fore on Nov. 20 in the journal Scientific Reports:

To understand the idea, first a reminder of what happens when you drink alcohol, physiologically.

Alcohol is metabolized by the enzyme alcohol dehydrogenase in the gut and then in the liver. That turns it into acetaldehyde, a toxic metabolite. In most of us, aldehyde dehydrogenase (ALDH) quickly metabolizes acetaldehyde to the inert acetate, which can be safely excreted.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

Scientific Reports

So let’s do some math. To make the numbers easy, let’s say you drank a liter of Australian wine, taking in 50 mg of quercetin glucuronide.

How much of that gets into your bloodstream? Some studies suggest a bioavailability of less than 1%, which basically means none and should probably put the quercetin hypothesis to bed. But there is some variation here too; it seems to depend on the form of quercetin you ingest.

Let’s say all 50 mg gets into your bloodstream. What blood concentration would that lead to? Well, I’ll keep the stoichiometry in the graphics and just say that if we assume that the volume of distribution of the compound is restricted to plasma alone, then you could achieve similar concentrations to what was done in petri dishes during this study.

Dr. F. Perry Wilson

Dr. 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.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Robert Louis Stevenson famously said, “Wine is bottled poetry.” And I think it works quite well. I’ve had wines that are simple, elegant, and unpretentious like Emily Dickinson, and passionate and mysterious like Pablo Neruda. And I’ve had wines that are more analogous to the limerick you might read scrawled on a rest-stop bathroom wall. Those ones give me headaches.

Wine headaches are on my mind this week, not only because of the incoming tide of Beaujolais nouveau, but because of a new study which claims to have finally explained the link between wine consumption and headaches – and apparently it’s not just the alcohol.

Headaches are common, and headaches after drinking alcohol are particularly common. An interesting epidemiologic phenomenon, not yet adequately explained, is why red wine is associated with more headache than other forms of alcohol. There have been many studies fingering many suspects, from sulfites to tannins to various phenolic compounds, but none have really provided a concrete explanation for what might be going on.

A new hypothesis came to the fore on Nov. 20 in the journal Scientific Reports:

To understand the idea, first a reminder of what happens when you drink alcohol, physiologically.

Alcohol is metabolized by the enzyme alcohol dehydrogenase in the gut and then in the liver. That turns it into acetaldehyde, a toxic metabolite. In most of us, aldehyde dehydrogenase (ALDH) quickly metabolizes acetaldehyde to the inert acetate, which can be safely excreted.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

Scientific Reports

So let’s do some math. To make the numbers easy, let’s say you drank a liter of Australian wine, taking in 50 mg of quercetin glucuronide.

How much of that gets into your bloodstream? Some studies suggest a bioavailability of less than 1%, which basically means none and should probably put the quercetin hypothesis to bed. But there is some variation here too; it seems to depend on the form of quercetin you ingest.

Let’s say all 50 mg gets into your bloodstream. What blood concentration would that lead to? Well, I’ll keep the stoichiometry in the graphics and just say that if we assume that the volume of distribution of the compound is restricted to plasma alone, then you could achieve similar concentrations to what was done in petri dishes during this study.

Dr. F. Perry Wilson

Dr. 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.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Robert Louis Stevenson famously said, “Wine is bottled poetry.” And I think it works quite well. I’ve had wines that are simple, elegant, and unpretentious like Emily Dickinson, and passionate and mysterious like Pablo Neruda. And I’ve had wines that are more analogous to the limerick you might read scrawled on a rest-stop bathroom wall. Those ones give me headaches.

Wine headaches are on my mind this week, not only because of the incoming tide of Beaujolais nouveau, but because of a new study which claims to have finally explained the link between wine consumption and headaches – and apparently it’s not just the alcohol.

Headaches are common, and headaches after drinking alcohol are particularly common. An interesting epidemiologic phenomenon, not yet adequately explained, is why red wine is associated with more headache than other forms of alcohol. There have been many studies fingering many suspects, from sulfites to tannins to various phenolic compounds, but none have really provided a concrete explanation for what might be going on.

A new hypothesis came to the fore on Nov. 20 in the journal Scientific Reports:

To understand the idea, first a reminder of what happens when you drink alcohol, physiologically.

Alcohol is metabolized by the enzyme alcohol dehydrogenase in the gut and then in the liver. That turns it into acetaldehyde, a toxic metabolite. In most of us, aldehyde dehydrogenase (ALDH) quickly metabolizes acetaldehyde to the inert acetate, which can be safely excreted.

Dr. F. Perry Wilson

Dr. F. Perry Wilson

Scientific Reports

So let’s do some math. To make the numbers easy, let’s say you drank a liter of Australian wine, taking in 50 mg of quercetin glucuronide.

How much of that gets into your bloodstream? Some studies suggest a bioavailability of less than 1%, which basically means none and should probably put the quercetin hypothesis to bed. But there is some variation here too; it seems to depend on the form of quercetin you ingest.

Let’s say all 50 mg gets into your bloodstream. What blood concentration would that lead to? Well, I’ll keep the stoichiometry in the graphics and just say that if we assume that the volume of distribution of the compound is restricted to plasma alone, then you could achieve similar concentrations to what was done in petri dishes during this study.

Dr. F. Perry Wilson

Dr. 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.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

UnitedHealthcare (UHC) is the latest payer accused of using artificial intelligence (AI) to deny patient claims by trading “real doctors’ recommendations” for a flawed algorithm to save money.

In a class action suit filed in Minnesota district court, the attorneys for the families of two deceased UHC Medicare Advantage plan policyholders say that the company uses the technology to systematically deny skilled nursing facility (SNF) claims and shirk its responsibility to adhere to Medicare’s coverage determination standards.

The case raises ethical and legal questions about whether AI can replace or supplement human tasks and interactions, particularly in a field as complex as health care. California-based public advocacy firm Clarkson Law filed a similar complaint against Cigna earlier this year and has previously sued tech giants Google and ChatGPT creator OpenAI for harvesting Internet users’ data to train their AI systems.

Clarkson Law represents the plaintiffs and says that the policyholders had to pay thousands in out-of-pocket costs or forgo the recommended postacute care owing to UHC’s faulty AI model, nH Predict. The tool has a 90% error rate, says the lawsuit, as evidenced by the number of claims that are reversed following review by a medical professional. Still, just 0.2% of policyholders appeal the denials.

nH Predict was created by naviHealth and was acquired by UnitedHealth Group, UHC’s parent company, in 2020. In a statement to Bloomberg Law, a spokesperson for naviHealth said that the lawsuit has no merit and the model was not used for making coverage determinations.

According to the complaint, nH Predict determines the appropriate amount of SNF, home health, or rehabilitation services a patient requires on the basis of the diagnosis, age, and living situation. The model compares the patient with its database of 6 million patients and estimates the ideal length of stay and target discharge date, “pinpointing the precise moment when [UHC] will cut off payment for a patient’s treatment.”

The lawsuit says that employees are instructed to strictly adhere to the AI model’s predictions, and those who do not are disciplined and terminated, even when additional care for the patient is warranted. Employees are told that the generated reports contain proprietary information and that they cannot share them with physicians and patients who inquire about extending care.

“Every patient is entitled to a nuanced evaluation of their health care needs,” Zarrina Ozari, senior associate at Clarkson Law, said in a prepared statement. “By replacing licensed practitioners with unchecked AI, UHC is telling its patients that they are completely interchangeable with one another and undervaluing the expertise of the physicians devoted to key elements of care.”

According to the complaint, Gene Lokken fell in May 2022 and fractured his leg and ankle. After a 1-month SNF stay, the 91-year-old man’s doctor ordered physical therapy. However, the insurer said Mr. Lokken was safe to be discharged home two and a half weeks later, conflicting with a physical therapist’s notes that indicated he still had paralyzed and weak muscles. The insurer denied Mr. Lokken’s appeal. He remained in the facility for another year until his death, paying about $150,000 in out-of-pocket expenses, according to the lawsuit.

Another patient, Dale H. Tetzloff, initially spent just 20 days in a SNF for stroke rehabilitation before UHC denied coverage. An appeal later extended the stay to 40 days, short of the 100 days recommended by his physician. Requests for further extensions were unsuccessful, and Mr. Tetzloff ultimately paid about $70,000 in out-of-pocket expenses over the next 10 months, according to the complaint.

New federal rules prohibit Medicare Advantage plans from relying on an algorithm or software to make medically necessary determinations instead of an individual’s specific circumstances. Any medical necessity denial must be “reviewed by a physician or other appropriate health care professional with expertise in the field of medicine or health care that is appropriate for the service at issue.”

Clarkson is demanding a jury trial and has asked the court to certify the case as a federal class action, which could open the suit to any U.S. resident who purchased a UHC Medicare Advantage plan in the past 4 years.

A version of this article appeared on Medscape.com.

UnitedHealthcare (UHC) is the latest payer accused of using artificial intelligence (AI) to deny patient claims by trading “real doctors’ recommendations” for a flawed algorithm to save money.

In a class action suit filed in Minnesota district court, the attorneys for the families of two deceased UHC Medicare Advantage plan policyholders say that the company uses the technology to systematically deny skilled nursing facility (SNF) claims and shirk its responsibility to adhere to Medicare’s coverage determination standards.

The case raises ethical and legal questions about whether AI can replace or supplement human tasks and interactions, particularly in a field as complex as health care. California-based public advocacy firm Clarkson Law filed a similar complaint against Cigna earlier this year and has previously sued tech giants Google and ChatGPT creator OpenAI for harvesting Internet users’ data to train their AI systems.

Clarkson Law represents the plaintiffs and says that the policyholders had to pay thousands in out-of-pocket costs or forgo the recommended postacute care owing to UHC’s faulty AI model, nH Predict. The tool has a 90% error rate, says the lawsuit, as evidenced by the number of claims that are reversed following review by a medical professional. Still, just 0.2% of policyholders appeal the denials.

nH Predict was created by naviHealth and was acquired by UnitedHealth Group, UHC’s parent company, in 2020. In a statement to Bloomberg Law, a spokesperson for naviHealth said that the lawsuit has no merit and the model was not used for making coverage determinations.

According to the complaint, nH Predict determines the appropriate amount of SNF, home health, or rehabilitation services a patient requires on the basis of the diagnosis, age, and living situation. The model compares the patient with its database of 6 million patients and estimates the ideal length of stay and target discharge date, “pinpointing the precise moment when [UHC] will cut off payment for a patient’s treatment.”

The lawsuit says that employees are instructed to strictly adhere to the AI model’s predictions, and those who do not are disciplined and terminated, even when additional care for the patient is warranted. Employees are told that the generated reports contain proprietary information and that they cannot share them with physicians and patients who inquire about extending care.

“Every patient is entitled to a nuanced evaluation of their health care needs,” Zarrina Ozari, senior associate at Clarkson Law, said in a prepared statement. “By replacing licensed practitioners with unchecked AI, UHC is telling its patients that they are completely interchangeable with one another and undervaluing the expertise of the physicians devoted to key elements of care.”

According to the complaint, Gene Lokken fell in May 2022 and fractured his leg and ankle. After a 1-month SNF stay, the 91-year-old man’s doctor ordered physical therapy. However, the insurer said Mr. Lokken was safe to be discharged home two and a half weeks later, conflicting with a physical therapist’s notes that indicated he still had paralyzed and weak muscles. The insurer denied Mr. Lokken’s appeal. He remained in the facility for another year until his death, paying about $150,000 in out-of-pocket expenses, according to the lawsuit.

Another patient, Dale H. Tetzloff, initially spent just 20 days in a SNF for stroke rehabilitation before UHC denied coverage. An appeal later extended the stay to 40 days, short of the 100 days recommended by his physician. Requests for further extensions were unsuccessful, and Mr. Tetzloff ultimately paid about $70,000 in out-of-pocket expenses over the next 10 months, according to the complaint.

New federal rules prohibit Medicare Advantage plans from relying on an algorithm or software to make medically necessary determinations instead of an individual’s specific circumstances. Any medical necessity denial must be “reviewed by a physician or other appropriate health care professional with expertise in the field of medicine or health care that is appropriate for the service at issue.”

Clarkson is demanding a jury trial and has asked the court to certify the case as a federal class action, which could open the suit to any U.S. resident who purchased a UHC Medicare Advantage plan in the past 4 years.

A version of this article appeared on Medscape.com.

UnitedHealthcare (UHC) is the latest payer accused of using artificial intelligence (AI) to deny patient claims by trading “real doctors’ recommendations” for a flawed algorithm to save money.

In a class action suit filed in Minnesota district court, the attorneys for the families of two deceased UHC Medicare Advantage plan policyholders say that the company uses the technology to systematically deny skilled nursing facility (SNF) claims and shirk its responsibility to adhere to Medicare’s coverage determination standards.

The case raises ethical and legal questions about whether AI can replace or supplement human tasks and interactions, particularly in a field as complex as health care. California-based public advocacy firm Clarkson Law filed a similar complaint against Cigna earlier this year and has previously sued tech giants Google and ChatGPT creator OpenAI for harvesting Internet users’ data to train their AI systems.

Clarkson Law represents the plaintiffs and says that the policyholders had to pay thousands in out-of-pocket costs or forgo the recommended postacute care owing to UHC’s faulty AI model, nH Predict. The tool has a 90% error rate, says the lawsuit, as evidenced by the number of claims that are reversed following review by a medical professional. Still, just 0.2% of policyholders appeal the denials.

nH Predict was created by naviHealth and was acquired by UnitedHealth Group, UHC’s parent company, in 2020. In a statement to Bloomberg Law, a spokesperson for naviHealth said that the lawsuit has no merit and the model was not used for making coverage determinations.

According to the complaint, nH Predict determines the appropriate amount of SNF, home health, or rehabilitation services a patient requires on the basis of the diagnosis, age, and living situation. The model compares the patient with its database of 6 million patients and estimates the ideal length of stay and target discharge date, “pinpointing the precise moment when [UHC] will cut off payment for a patient’s treatment.”

The lawsuit says that employees are instructed to strictly adhere to the AI model’s predictions, and those who do not are disciplined and terminated, even when additional care for the patient is warranted. Employees are told that the generated reports contain proprietary information and that they cannot share them with physicians and patients who inquire about extending care.

“Every patient is entitled to a nuanced evaluation of their health care needs,” Zarrina Ozari, senior associate at Clarkson Law, said in a prepared statement. “By replacing licensed practitioners with unchecked AI, UHC is telling its patients that they are completely interchangeable with one another and undervaluing the expertise of the physicians devoted to key elements of care.”

According to the complaint, Gene Lokken fell in May 2022 and fractured his leg and ankle. After a 1-month SNF stay, the 91-year-old man’s doctor ordered physical therapy. However, the insurer said Mr. Lokken was safe to be discharged home two and a half weeks later, conflicting with a physical therapist’s notes that indicated he still had paralyzed and weak muscles. The insurer denied Mr. Lokken’s appeal. He remained in the facility for another year until his death, paying about $150,000 in out-of-pocket expenses, according to the lawsuit.

Another patient, Dale H. Tetzloff, initially spent just 20 days in a SNF for stroke rehabilitation before UHC denied coverage. An appeal later extended the stay to 40 days, short of the 100 days recommended by his physician. Requests for further extensions were unsuccessful, and Mr. Tetzloff ultimately paid about $70,000 in out-of-pocket expenses over the next 10 months, according to the complaint.

New federal rules prohibit Medicare Advantage plans from relying on an algorithm or software to make medically necessary determinations instead of an individual’s specific circumstances. Any medical necessity denial must be “reviewed by a physician or other appropriate health care professional with expertise in the field of medicine or health care that is appropriate for the service at issue.”

Clarkson is demanding a jury trial and has asked the court to certify the case as a federal class action, which could open the suit to any U.S. resident who purchased a UHC Medicare Advantage plan in the past 4 years.

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.

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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Download the PDF

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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

 

 

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

 

 

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

 

 

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.