Cardiology News

The known reduction in the risk of type 2 diabetes associated with adoption of the Mediterranean diet appears specifically attributed to its beneficial effects on some key factors, a new study published online in JAMA Network Open reveals.

While a reduction in body mass index may be somewhat obvious, other mechanisms include beneficial effects on insulin resistance, lipoprotein metabolism, and inflammation.

However, the diet’s antidiabetes effect does not appear to extend to people whose weight is considered healthy (BMI under 25 kg/m²), according to the findings.

“It is striking to see in these U.S. women how strong the long-term antidiabetic properties of a Mediterranean-type dietary pattern are,” senior author Samia Mora, MD, of the Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, said in an interview.

“While it was known that the Mediterranean diet has many health benefits in particular on metabolism and inflammation, it was not previously known which of these biological pathways may be contributing to the lower risk of diabetes and to what magnitude.

“Our findings support the idea that by improving their diet, people can improve their future risk of type 2 diabetes, particularly if they are overweight or have obesity,” she added.

“And it’s important to note that many of these changes don’t happen right away. While metabolism can change over a short period of time, our study indicates that there are longer term changes happening that may provide protection over decades.”
 

Mediterranean diet reduced diabetes risk in those with BMI ≥ 25 kg/m²

The Mediterranean diet, with an emphasis on healthy olive oil as the predominant source of oil, favors fruits, vegetables, legumes, nuts, seeds, fish, and dairy products, while limiting intake of red and processed meats as well as sweets.

The diet has been linked to as much as a 25%-30% reduction in the risk of diabetes in previous observational studies.

To investigate the precise mechanisms that underlie the prevention of diabetes, lead author Shafqat Ahmad, PhD, also of Harvard, and colleagues examined data from 25,317 healthy women participating in the Women’s Health Study who had baseline assessments between September 1992 and May 1995. They were a mean age of 52.9 years at baseline.

Over the course of the study, 2,307 participants developed type 2 diabetes.

With a mean follow-up of 19.8 years, those who had the highest self-reported adherence to the Mediterranean diet (a score ≥ 6 on a scale of 0-6) at baseline, had as much as a 30% lower risk of developing type 2 diabetes after multivariate adjustments, compared to those with a lower Mediterranean diet score (a score ≤ 3; hazard ratio, 0.70).

The diabetes-related biomarkers that contributed the most to the reduced risk were insulin resistance, accounting for 65% of the reduction, followed by BMI (55.5%), high-density lipoprotein measures (53%), and inflammation (52.5%).

Other factors, though to a lesser degree, included branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%).

Differences in hemoglobin A1c levels had a limited effect on the risk (2%).

Notably, a subgroup analysis looking at effects of the diet according to baseline BMI showed the reductions in type 2 diabetes associated with higher intake of the Mediterranean diet extended only to those with an above normal weight (BMI ≥ 25 kg/m²).

Dr. Mora noted that, as this was not a prespecified analysis, these findings should be viewed as hypothesis-generating, but are consistent with the well-known increase in diabetes risk seen with a higher BMI.

“[The finding] fits with the biology and pathogenesis of type 2 diabetes that is driven in large part by excess weight, in particular for visceral adiposity and its resulting metabolic dysregulation and inflammation,” she said.

“We know from other studies, such as the Nurses’ Health Study, that the risk for type 2 diabetes in women increases even at BMI levels below 25 kg/m², but the risk goes up exponentially at around a BMI of 25 and higher.”

Strong role of insulin resistance a surprise

The strong role of insulin resistance was a surprise, Dr. Mora added.

“We were surprised that insulin resistance, measured by a simple blood biomarker, would have the strongest mediating effect – even stronger than BMI – for the Mediterranean diet on risk of diabetes,” she noted.

“This could represent an opportunity to intervene earlier and more intensively on improving insulin resistance through dietary approaches such as the Mediterranean diet, especially [because] insulin resistance can precede by years and decades the overt hyperglycemia and clinical diagnosis of diabetes.”

Yet another surprise was that A1c had no substantial mediating effect on the reduction of diabetes risk with the Mediterranean diet.

“This could suggest that the cat is out of the bag by the time the A1c rises,” Dr. Mora observed.

A study limitation is that the Women’s Health Study consisted of well-educated U.S. women who were health professionals and predominantly White, so the results may not be generalizable to men or individuals of other races or ethnicities.

In addition, BMI was self-reported and participants were not uniformly screened for diabetes, therefore surveillance bias could be possible.

However, the findings suggest that “even a small increase in adherence to the Mediterranean diet has substantial benefits over many years in preventing diabetes, among many other health benefits such as lowering insulin resistance and inflammation, improving lipid metabolism, and lowering blood pressure,” Mora said.

“And of course, the more the adherence, the more the benefit.” 

The study received support through grants from the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Heart Association, and the Molino Family Trust. A coauthor is listed as a coinventor on patents held by Brigham and Women’s Hospital related to the use of inflammatory biomarkers in cardiovascular disease (licensed to AstraZeneca and Siemens).

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

The known reduction in the risk of type 2 diabetes associated with adoption of the Mediterranean diet appears specifically attributed to its beneficial effects on some key factors, a new study published online in JAMA Network Open reveals.

While a reduction in body mass index may be somewhat obvious, other mechanisms include beneficial effects on insulin resistance, lipoprotein metabolism, and inflammation.

However, the diet’s antidiabetes effect does not appear to extend to people whose weight is considered healthy (BMI under 25 kg/m²), according to the findings.

“It is striking to see in these U.S. women how strong the long-term antidiabetic properties of a Mediterranean-type dietary pattern are,” senior author Samia Mora, MD, of the Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, said in an interview.

“While it was known that the Mediterranean diet has many health benefits in particular on metabolism and inflammation, it was not previously known which of these biological pathways may be contributing to the lower risk of diabetes and to what magnitude.

“Our findings support the idea that by improving their diet, people can improve their future risk of type 2 diabetes, particularly if they are overweight or have obesity,” she added.

“And it’s important to note that many of these changes don’t happen right away. While metabolism can change over a short period of time, our study indicates that there are longer term changes happening that may provide protection over decades.”
 

Mediterranean diet reduced diabetes risk in those with BMI ≥ 25 kg/m²

The Mediterranean diet, with an emphasis on healthy olive oil as the predominant source of oil, favors fruits, vegetables, legumes, nuts, seeds, fish, and dairy products, while limiting intake of red and processed meats as well as sweets.

The diet has been linked to as much as a 25%-30% reduction in the risk of diabetes in previous observational studies.

To investigate the precise mechanisms that underlie the prevention of diabetes, lead author Shafqat Ahmad, PhD, also of Harvard, and colleagues examined data from 25,317 healthy women participating in the Women’s Health Study who had baseline assessments between September 1992 and May 1995. They were a mean age of 52.9 years at baseline.

Over the course of the study, 2,307 participants developed type 2 diabetes.

With a mean follow-up of 19.8 years, those who had the highest self-reported adherence to the Mediterranean diet (a score ≥ 6 on a scale of 0-6) at baseline, had as much as a 30% lower risk of developing type 2 diabetes after multivariate adjustments, compared to those with a lower Mediterranean diet score (a score ≤ 3; hazard ratio, 0.70).

The diabetes-related biomarkers that contributed the most to the reduced risk were insulin resistance, accounting for 65% of the reduction, followed by BMI (55.5%), high-density lipoprotein measures (53%), and inflammation (52.5%).

Other factors, though to a lesser degree, included branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%).

Differences in hemoglobin A1c levels had a limited effect on the risk (2%).

Notably, a subgroup analysis looking at effects of the diet according to baseline BMI showed the reductions in type 2 diabetes associated with higher intake of the Mediterranean diet extended only to those with an above normal weight (BMI ≥ 25 kg/m²).

Dr. Mora noted that, as this was not a prespecified analysis, these findings should be viewed as hypothesis-generating, but are consistent with the well-known increase in diabetes risk seen with a higher BMI.

“[The finding] fits with the biology and pathogenesis of type 2 diabetes that is driven in large part by excess weight, in particular for visceral adiposity and its resulting metabolic dysregulation and inflammation,” she said.

“We know from other studies, such as the Nurses’ Health Study, that the risk for type 2 diabetes in women increases even at BMI levels below 25 kg/m², but the risk goes up exponentially at around a BMI of 25 and higher.”

Strong role of insulin resistance a surprise

The strong role of insulin resistance was a surprise, Dr. Mora added.

“We were surprised that insulin resistance, measured by a simple blood biomarker, would have the strongest mediating effect – even stronger than BMI – for the Mediterranean diet on risk of diabetes,” she noted.

“This could represent an opportunity to intervene earlier and more intensively on improving insulin resistance through dietary approaches such as the Mediterranean diet, especially [because] insulin resistance can precede by years and decades the overt hyperglycemia and clinical diagnosis of diabetes.”

Yet another surprise was that A1c had no substantial mediating effect on the reduction of diabetes risk with the Mediterranean diet.

“This could suggest that the cat is out of the bag by the time the A1c rises,” Dr. Mora observed.

A study limitation is that the Women’s Health Study consisted of well-educated U.S. women who were health professionals and predominantly White, so the results may not be generalizable to men or individuals of other races or ethnicities.

In addition, BMI was self-reported and participants were not uniformly screened for diabetes, therefore surveillance bias could be possible.

However, the findings suggest that “even a small increase in adherence to the Mediterranean diet has substantial benefits over many years in preventing diabetes, among many other health benefits such as lowering insulin resistance and inflammation, improving lipid metabolism, and lowering blood pressure,” Mora said.

“And of course, the more the adherence, the more the benefit.” 

The study received support through grants from the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Heart Association, and the Molino Family Trust. A coauthor is listed as a coinventor on patents held by Brigham and Women’s Hospital related to the use of inflammatory biomarkers in cardiovascular disease (licensed to AstraZeneca and Siemens).

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

The known reduction in the risk of type 2 diabetes associated with adoption of the Mediterranean diet appears specifically attributed to its beneficial effects on some key factors, a new study published online in JAMA Network Open reveals.

While a reduction in body mass index may be somewhat obvious, other mechanisms include beneficial effects on insulin resistance, lipoprotein metabolism, and inflammation.

However, the diet’s antidiabetes effect does not appear to extend to people whose weight is considered healthy (BMI under 25 kg/m²), according to the findings.

“It is striking to see in these U.S. women how strong the long-term antidiabetic properties of a Mediterranean-type dietary pattern are,” senior author Samia Mora, MD, of the Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, said in an interview.

“While it was known that the Mediterranean diet has many health benefits in particular on metabolism and inflammation, it was not previously known which of these biological pathways may be contributing to the lower risk of diabetes and to what magnitude.

“Our findings support the idea that by improving their diet, people can improve their future risk of type 2 diabetes, particularly if they are overweight or have obesity,” she added.

“And it’s important to note that many of these changes don’t happen right away. While metabolism can change over a short period of time, our study indicates that there are longer term changes happening that may provide protection over decades.”
 

Mediterranean diet reduced diabetes risk in those with BMI ≥ 25 kg/m²

The Mediterranean diet, with an emphasis on healthy olive oil as the predominant source of oil, favors fruits, vegetables, legumes, nuts, seeds, fish, and dairy products, while limiting intake of red and processed meats as well as sweets.

The diet has been linked to as much as a 25%-30% reduction in the risk of diabetes in previous observational studies.

To investigate the precise mechanisms that underlie the prevention of diabetes, lead author Shafqat Ahmad, PhD, also of Harvard, and colleagues examined data from 25,317 healthy women participating in the Women’s Health Study who had baseline assessments between September 1992 and May 1995. They were a mean age of 52.9 years at baseline.

Over the course of the study, 2,307 participants developed type 2 diabetes.

With a mean follow-up of 19.8 years, those who had the highest self-reported adherence to the Mediterranean diet (a score ≥ 6 on a scale of 0-6) at baseline, had as much as a 30% lower risk of developing type 2 diabetes after multivariate adjustments, compared to those with a lower Mediterranean diet score (a score ≤ 3; hazard ratio, 0.70).

The diabetes-related biomarkers that contributed the most to the reduced risk were insulin resistance, accounting for 65% of the reduction, followed by BMI (55.5%), high-density lipoprotein measures (53%), and inflammation (52.5%).

Other factors, though to a lesser degree, included branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%).

Differences in hemoglobin A1c levels had a limited effect on the risk (2%).

Notably, a subgroup analysis looking at effects of the diet according to baseline BMI showed the reductions in type 2 diabetes associated with higher intake of the Mediterranean diet extended only to those with an above normal weight (BMI ≥ 25 kg/m²).

Dr. Mora noted that, as this was not a prespecified analysis, these findings should be viewed as hypothesis-generating, but are consistent with the well-known increase in diabetes risk seen with a higher BMI.

“[The finding] fits with the biology and pathogenesis of type 2 diabetes that is driven in large part by excess weight, in particular for visceral adiposity and its resulting metabolic dysregulation and inflammation,” she said.

“We know from other studies, such as the Nurses’ Health Study, that the risk for type 2 diabetes in women increases even at BMI levels below 25 kg/m², but the risk goes up exponentially at around a BMI of 25 and higher.”

Strong role of insulin resistance a surprise

The strong role of insulin resistance was a surprise, Dr. Mora added.

“We were surprised that insulin resistance, measured by a simple blood biomarker, would have the strongest mediating effect – even stronger than BMI – for the Mediterranean diet on risk of diabetes,” she noted.

“This could represent an opportunity to intervene earlier and more intensively on improving insulin resistance through dietary approaches such as the Mediterranean diet, especially [because] insulin resistance can precede by years and decades the overt hyperglycemia and clinical diagnosis of diabetes.”

Yet another surprise was that A1c had no substantial mediating effect on the reduction of diabetes risk with the Mediterranean diet.

“This could suggest that the cat is out of the bag by the time the A1c rises,” Dr. Mora observed.

A study limitation is that the Women’s Health Study consisted of well-educated U.S. women who were health professionals and predominantly White, so the results may not be generalizable to men or individuals of other races or ethnicities.

In addition, BMI was self-reported and participants were not uniformly screened for diabetes, therefore surveillance bias could be possible.

However, the findings suggest that “even a small increase in adherence to the Mediterranean diet has substantial benefits over many years in preventing diabetes, among many other health benefits such as lowering insulin resistance and inflammation, improving lipid metabolism, and lowering blood pressure,” Mora said.

“And of course, the more the adherence, the more the benefit.” 

The study received support through grants from the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Heart Association, and the Molino Family Trust. A coauthor is listed as a coinventor on patents held by Brigham and Women’s Hospital related to the use of inflammatory biomarkers in cardiovascular disease (licensed to AstraZeneca and Siemens).

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

While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

While stressing the urgent need to vaccinate the whole U.S. population, infectious disease experts and medical ethicists are raising questions about the clinical trials needed to answer important questions about the new COVID-19 vaccines.

In a statement released on Nov. 20, Barbara Alexander, MD, president of the Infectious Diseases Society of America (IDSA) and a professor at Duke University, Durham, N.C., commented on Pfizer and BioNTech’s application to the Food and Drug Administration for an emergency use authorization (EUA) for its COVID-19 vaccine. Besides emphasizing the need for a transparent review of the companies’ trial data prior to the FDA’s granting an EUA, she said, “If emergency use authorization is granted, clinical trials and data collection must continue.”

In an interview, Dr. Alexander said she is convinced that both Pfizer and Moderna, which is also expected to seek an EUA soon, will continue their clinical trials to monitor the long-term safety and efficacy of their vaccines.

“The EUA guidance for COVID vaccine authorization is very clear that clinical trials will move forward,” she said. “Any EUA request would have to include a strategy to ensure that the long-term safety and efficacy of a vaccine could be monitored. I see no evidence that either Pfizer or Moderna is not prepared to follow those regulations.”

Eventually, she added, the drug makers will have to seek full FDA approval to replace an EUA, which as its name signifies, is designed for public health emergencies. “The EUA is a tool to help us get the vaccine into circulation and have it start working as quickly as possible in the current health crisis,” she said. “But once the crisis is over, if the sponsors want to continue to market their vaccines, they have to go forward and get full approval.”

Medical ethicists, however, point out there may be ethical and practical dilemmas involved in continuing or initiating clinical trials once a vaccine has been approved for use even on an emergency basis.

In a commentary in Annals of Internal Medicine, Rafael Dal-Re, MD, PhD, Arthur L. Caplan, PhD, and two other ethicists stipulated that the pandemic requires early licensing and deployment of COVID-19 vaccines. Nevertheless, they noted, additional months of data are required to establish the long-term efficacy and safety of the vaccines. “Moreover, early deployment could interfere with the acquisition of long-term data,” both on these vaccines and on others coming through the pipeline, they wrote.

In countries where an approved vaccine is deployed, the ethicists noted, investigators must inform participants in an ongoing trial about the approved vaccine’s status and ask if they want to continue in the study. If enough participants decline, the trial might have to be terminated early. At that point, researchers may not have sufficient long-term data to identify late-term safety issues, determine how long efficacy lasts, determine whether waning immunity is associated with reduced levels of antibodies, or identify the level of neutralizing antibodies that correlates with immunity.

Moreover, they observed, long-term trials are especially important for vaccines that use mRNA technology, because less is known about them than about traditional kinds of vaccines.

The authors also pointed out that early licensing of any vaccine might make it harder to evaluate vaccines that haven’t yet been approved. “Once a vaccine is licensed, new placebo-controlled RCTs [randomized controlled trials] of other vaccines will not be acceptable ethically, and noninferiority RCTs will be the most likely alternative.

“The goal of noninferiority trials will be to demonstrate that the immune response (that is, neutralizing antibody titers or levels) of the candidate vaccine is not inferior to that of the approved vaccine within a prespecified margin, which the FDA has established as less than 10% for COVID-19 vaccines,” the authors noted. 
 

More data with more study designs

Dial Hewlett Jr., MD, medical director for disease control services, Westchester County Department of Health, White Plains, N.Y., said in an interview that the ethicists raise important issues that have been discussed in other forums, including a recent webinar of the National Academy of Medicine.

“As the authors point out, once you have a vaccine that has been shown to be effective and safe, it’s no longer ethical to enroll people in placebo trials,” he said.

Therefore, he said, Pfizer and Moderna will undoubtedly offer their vaccines to the people in their studies’ placebo groups after the vaccines receive an EUA. Then they will follow everyone who has been vaccinated for 2 years to determine long-term safety. Efficacy will also continue to be measured as an adjunct of safety, he said.

With regard to the difficulty of reconsenting individuals to enter a new clinical trial after a vaccine has been approved, he said, “I’d agree that trying to get all the same participants to come into another study would be a challenge. You can, however, design studies that will allow you to obtain the same information. You will have a large number of people out there who haven’t been vaccinated, and you can do single-arm longitudinal studies and measure a number of things in the individuals who are enrolled in those studies,” he said.

“You can look at the immunologic markers, both antibody and T-cell. You can follow these individuals longitudinally to see if they do develop disease over a period of time. If they do, you can determine what their levels of response were,” he added. “So there are opportunities to design studies that would give you some of the same information, although it would not be in the same population that was in the randomized trials.”

For newer vaccines that have yet to be tested, he said, developers can compare “historical controls” from the trials of approved vaccines, i.e., data from the unvaccinated participants in those studies, with the data from inoculating people with the novel agents. The historical data can be sex- and age-matched, among other things, to individuals in the new trials. Moreover, because the study protocols have been harmonized for all trials under Operation Warp Speed, it doesn’t matter what kind of vaccine they’re testing, he said.

It may be necessary to do additional studies to find out how long immunity lasts after people have been vaccinated, Dr. Hewlett pointed out.

“You may have a different trial design. You don’t need a control arm to determine how long immunity lasts. You’re just comparing the patients who were vaccinated to nothing,” he said. “So you could have a single-arm trial on a group of people who consent to be immunized and followed. You can see what their antibody levels are and other surrogate markers, and you can see when they might develop disease, if they do. You’d need a large sample, but you can do that.”

Dr. Hewlett noted that additional studies will be required to determine whether the new vaccines stop transmission of the coronavirus or just prevent symptoms of COVID-19. Until it’s established that a vaccine halts transmission or the country achieves herd immunity, he said, “we’ll still have to wear masks and take other precautions, because a significant portion of people will still be at risk.”
 

‘A lot of redundancy’

Dr. Alexander emphasized that any safety or efficacy issues with the first COVID-19 vaccines must be identified before the vaccine is offered to a large portion of the U.S. population.

“While the data from the Pfizer and Moderna trials are said to be favorable, we at IDSA want to make sure that whatever vaccine comes to market is safe,” she said. “Having an unsafe vaccine on the market would be worse than no vaccine, because you’re compromising the public confidence. We have to make sure the public trusts the process and that sufficient data have been evaluated to ensure the vaccine is safe and efficacious.

“I believe the FDA is being very careful and thoughtful in [its] response,” Dr. Alexander said. “They realize how important it is to get a vaccine and save lives. While they’re doing things differently and moving much faster than before, they’re still trying to be thoughtful and reasonable. They don’t seem to be putting people at risk or circumventing the regulatory standards.”

Moreover, she pointed out, the FDA’s Vaccines and Related Biological Products Advisory Committee, which is expected to meet on Dec. 10, will review the trial data before the agency grants an EUA to Pfizer or Moderna. Then the FDA will post the data publicly.

The next step is for the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention to look at the data and decide who in the United States should receive the vaccine first, she pointed out. And both Pfizer and Moderna have shown their data to advisory panels of outside experts.

“There’s a lot of redundancy, and a lot of people are looking at the data,” Dr. Alexander said. “So I don’t think we’re cutting corners to get it out there more quickly.”

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

On Monday, members of an influential federal panel delved into the challenges ahead in deciding who will get the first doses of COVID-19 vaccines, including questions about which healthcare workers need those initial vaccinations the most.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) did not take any votes or seek to establish formal positions. Instead, the meeting served as a forum for experts to discuss the thorny issues ahead. The US Food and Drug Administration (FDA) could make a decision next month regarding clearance for the first COVID-19 vaccine.

An FDA advisory committee will meet December 10 to review the request for emergency use authorization (EUA) of a COVID-19 vaccine from Pfizer, in partnership with BioNTech. Moderna Inc said on November 16 that it expects to soon ask the FDA for an EUA of its rival COVID vaccine.

ACIP will face a two-part task after the FDA clears COVID-19 vaccines, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. ACIP will need to first decide whether to recommend use of the vaccine and then address the “complicated and difficult” question of which groups should get the initial limited quantities.

“There aren’t any perfect decisions,” she told the ACIP members. “I know this is something that most of you didn’t anticipate doing, making these kinds of huge decisions in the midst of a pandemic.”

There has been considerable public discussion of prioritization of COVID-19 vaccines, including a set of recommendations offered by a special committee created by the National Academies of Sciences, Engineering and Medicine. In addition, CDC staff and members of ACIP outlined what they termed the “four ethical principles” meant to guide these decisions in a November 23 report in the agency’s Morbidity and Mortality Weekly Report. These four principles are to maximize benefits and minimize harms; promote justice; mitigate health inequities; and promote transparency.

But as the issuing of the first EUA nears, it falls to ACIP to move beyond endorsing broad goals. The panel will need to make decisions as to which groups will have to wait for COVID-19 vaccines.

ACIP members on Monday delved into these kinds of more detailed questions, using a proposed three-stage model as a discussion point.

In phase 1a of this model, healthcare workers and residents of long-term care facilities would be the first people to be vaccinated. Phase 1b would include those deemed essential workers, including police officers, firefighters, and those in education, transportation, food, and agriculture sectors. Phase 1c would include adults with high-risk medical conditions and those aged 65 years and older.

ACIP member Grace M. Lee, MD, MPH, of Stanford University, Stanford, California, questioned whether healthcare workers who are not seeing patients in person should wait to get the vaccines. There has been a marked rise in the use of telehealth during the pandemic, which has spared some clinicians from in-person COVID-19 patient visits in their practices.

“Close partnership with our public health colleagues will be critically important to make sure that we are not trying to vaccinate 100% of our healthcare workforce, if some proportion of our workforce can work from home,” Lee said.

ACIP member Pablo Sánchez, MD, of the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, concurred. Some clinicians, he noted, may have better access to personal protective equipment than others, he said.

“Unfortunately, not all healthcare workers are equal in terms of risk,” Sánchez said. “Within institutions, we’re going to have to prioritize which ones will get” the vaccine.

Clinicians may also make judgments about their own risk and need for early access to COVID-19 vaccinations, Sánchez said.

“I’m 66, and I’d rather give it to somebody much older and sicker than me,” he said.
 

Broader access

Fairly large populations will essentially be competing for limited doses of the first vaccines to reach the market.

The overlap is significant in the four priority groups put forward by CDC. The CDC staff estimated that about 21 million people would fall into the healthcare personnel category, which includes hospital staff, pharmacists, and those working in long-term care facilities. There are about 87 million people in the essential workers groups. More than 100 million adults in the United States, such as those with diabetes and cancers, fall into the high-risk medical conditions group. Another 53 million people are aged 65 and older.

Department of Health and Human Services Secretary Alex Azar on November 18 said the federal government expects to have about 40 million doses of these two vaccines by the end of December, which is enough to provide the two-dose regimen for about 20 million. If all goes as expected, Pfizer and Moderna will ramp up production.

Moderna has said that it expects by the end of this year to have approximately 20 million doses of its vaccine ready to ship in the United States and that it is on track to manufacture 500 million to 1 billion doses globally in 2021. Pfizer and BioNTech have said they expect to produce globally up to 50 million doses in 2020 and up to 1.3 billion doses by the end of 2021.

At the Monday meeting, several ACIP panelists stressed the need to ensure that essential workers get early doses of vaccines.

In many cases, these workers serve in jobs with significant public interaction and live in poor communities. They put themselves and their families at risk. Many of them lack the resources to take precautions available to those better able to isolate, said ACIP member Beth Bell, MD, MPH, of the University of Washington, Seattle, Washington.

“These essential workers are out there putting themselves at risk to allow the rest of us to socially distance,” she said. “Recognizing that not all of them may want to be vaccinated at this stage, we need to provide them with the opportunity early on in the process.”

In Bell’s view, the initial rollout of COVID-19 vaccines will send an important message about sharing this resource.

“If we’re serious about valuing equity, we need to have that baked in early on in the vaccination program,” she said.

Bell also said she was in favor of including people living in nursing homes in the initial wave of vaccinations. Concerns were raised about the frailty of this population.

“Given the mortality impact on the healthcare system from the number of nursing home residents that have been dying, I think on balance it makes sense to include them in phase 1a,” Bell said.

Other ACIP panelists said missteps with early vaccination of people in nursing homes could undermine faith in the treatments. Because of the ages and medical conditions of people in nursing homes, many of them may die after receiving the COVID-19 vaccine. Such deaths would not be associated with vaccine, but the medical community would not yet have evidence to disprove a connection.

There could be a backlash, with people falsely linking the death of a grandparent to the vaccine.

Fellow ACIP member Robert L. Atmar, MD, Baylor College of Medicine, Houston, Texas, was among those who had raised concerns about including people living in long-term care facilities in phase 1a. He said there are not yet enough data to judge the balance of benefits and harms of vaccination for this population.

The Pfizer and Moderna vaccines are “reactagenic,” meaning people may not feel well in the days after receiving the shots. The symptoms could lead to additional health evaluations of older people in nursing homes as clinicians try to figure out whether the patient’s reactions to the vaccine are caused by some condition or infection, Atmar said.

“Those of us who see these patients in the hospital recognize that there are often medical interventions that are done in the pursuit of a diagnosis, of a change in clinical status, that in and of themselves can lead to harm,” Atmar said.

Clinicians likely will have to encourage their patients of all ages to receive second doses of COVID-19 vaccines, despite the malaise they may provoke.

“We really need to make patients aware that this is not going to be a walk in the park. I mean, they’re going to know they had a vaccine, they’re probably not going to feel wonderful, but they’ve got to come back for that second dose,” said Sandra Adamson Fryhofer, MD, who represented the American Medical Association.

ACIP is expected to meet again to offer specific recommendations on the Pfizer and Moderna vaccines. ACIP’s recommendations trigger reimbursement processes, Azar said at a Tuesday press conference. ACIP’s work will inform decisions made by the federal government and governors about deploying shipments of COVID-19 vaccines, he said.

“At the end of the day, that is a decision, though, of the US government to make, which is where to recommend the prioritization,” Azar said. “It will be our nation’s governors in implementing the distribution plans to tell us” where to ship the vaccine.

This article first appeared on Medscape.com.

On Monday, members of an influential federal panel delved into the challenges ahead in deciding who will get the first doses of COVID-19 vaccines, including questions about which healthcare workers need those initial vaccinations the most.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) did not take any votes or seek to establish formal positions. Instead, the meeting served as a forum for experts to discuss the thorny issues ahead. The US Food and Drug Administration (FDA) could make a decision next month regarding clearance for the first COVID-19 vaccine.

An FDA advisory committee will meet December 10 to review the request for emergency use authorization (EUA) of a COVID-19 vaccine from Pfizer, in partnership with BioNTech. Moderna Inc said on November 16 that it expects to soon ask the FDA for an EUA of its rival COVID vaccine.

ACIP will face a two-part task after the FDA clears COVID-19 vaccines, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. ACIP will need to first decide whether to recommend use of the vaccine and then address the “complicated and difficult” question of which groups should get the initial limited quantities.

“There aren’t any perfect decisions,” she told the ACIP members. “I know this is something that most of you didn’t anticipate doing, making these kinds of huge decisions in the midst of a pandemic.”

There has been considerable public discussion of prioritization of COVID-19 vaccines, including a set of recommendations offered by a special committee created by the National Academies of Sciences, Engineering and Medicine. In addition, CDC staff and members of ACIP outlined what they termed the “four ethical principles” meant to guide these decisions in a November 23 report in the agency’s Morbidity and Mortality Weekly Report. These four principles are to maximize benefits and minimize harms; promote justice; mitigate health inequities; and promote transparency.

But as the issuing of the first EUA nears, it falls to ACIP to move beyond endorsing broad goals. The panel will need to make decisions as to which groups will have to wait for COVID-19 vaccines.

ACIP members on Monday delved into these kinds of more detailed questions, using a proposed three-stage model as a discussion point.

In phase 1a of this model, healthcare workers and residents of long-term care facilities would be the first people to be vaccinated. Phase 1b would include those deemed essential workers, including police officers, firefighters, and those in education, transportation, food, and agriculture sectors. Phase 1c would include adults with high-risk medical conditions and those aged 65 years and older.

ACIP member Grace M. Lee, MD, MPH, of Stanford University, Stanford, California, questioned whether healthcare workers who are not seeing patients in person should wait to get the vaccines. There has been a marked rise in the use of telehealth during the pandemic, which has spared some clinicians from in-person COVID-19 patient visits in their practices.

“Close partnership with our public health colleagues will be critically important to make sure that we are not trying to vaccinate 100% of our healthcare workforce, if some proportion of our workforce can work from home,” Lee said.

ACIP member Pablo Sánchez, MD, of the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, concurred. Some clinicians, he noted, may have better access to personal protective equipment than others, he said.

“Unfortunately, not all healthcare workers are equal in terms of risk,” Sánchez said. “Within institutions, we’re going to have to prioritize which ones will get” the vaccine.

Clinicians may also make judgments about their own risk and need for early access to COVID-19 vaccinations, Sánchez said.

“I’m 66, and I’d rather give it to somebody much older and sicker than me,” he said.
 

Broader access

Fairly large populations will essentially be competing for limited doses of the first vaccines to reach the market.

The overlap is significant in the four priority groups put forward by CDC. The CDC staff estimated that about 21 million people would fall into the healthcare personnel category, which includes hospital staff, pharmacists, and those working in long-term care facilities. There are about 87 million people in the essential workers groups. More than 100 million adults in the United States, such as those with diabetes and cancers, fall into the high-risk medical conditions group. Another 53 million people are aged 65 and older.

Department of Health and Human Services Secretary Alex Azar on November 18 said the federal government expects to have about 40 million doses of these two vaccines by the end of December, which is enough to provide the two-dose regimen for about 20 million. If all goes as expected, Pfizer and Moderna will ramp up production.

Moderna has said that it expects by the end of this year to have approximately 20 million doses of its vaccine ready to ship in the United States and that it is on track to manufacture 500 million to 1 billion doses globally in 2021. Pfizer and BioNTech have said they expect to produce globally up to 50 million doses in 2020 and up to 1.3 billion doses by the end of 2021.

At the Monday meeting, several ACIP panelists stressed the need to ensure that essential workers get early doses of vaccines.

In many cases, these workers serve in jobs with significant public interaction and live in poor communities. They put themselves and their families at risk. Many of them lack the resources to take precautions available to those better able to isolate, said ACIP member Beth Bell, MD, MPH, of the University of Washington, Seattle, Washington.

“These essential workers are out there putting themselves at risk to allow the rest of us to socially distance,” she said. “Recognizing that not all of them may want to be vaccinated at this stage, we need to provide them with the opportunity early on in the process.”

In Bell’s view, the initial rollout of COVID-19 vaccines will send an important message about sharing this resource.

“If we’re serious about valuing equity, we need to have that baked in early on in the vaccination program,” she said.

Bell also said she was in favor of including people living in nursing homes in the initial wave of vaccinations. Concerns were raised about the frailty of this population.

“Given the mortality impact on the healthcare system from the number of nursing home residents that have been dying, I think on balance it makes sense to include them in phase 1a,” Bell said.

Other ACIP panelists said missteps with early vaccination of people in nursing homes could undermine faith in the treatments. Because of the ages and medical conditions of people in nursing homes, many of them may die after receiving the COVID-19 vaccine. Such deaths would not be associated with vaccine, but the medical community would not yet have evidence to disprove a connection.

There could be a backlash, with people falsely linking the death of a grandparent to the vaccine.

Fellow ACIP member Robert L. Atmar, MD, Baylor College of Medicine, Houston, Texas, was among those who had raised concerns about including people living in long-term care facilities in phase 1a. He said there are not yet enough data to judge the balance of benefits and harms of vaccination for this population.

The Pfizer and Moderna vaccines are “reactagenic,” meaning people may not feel well in the days after receiving the shots. The symptoms could lead to additional health evaluations of older people in nursing homes as clinicians try to figure out whether the patient’s reactions to the vaccine are caused by some condition or infection, Atmar said.

“Those of us who see these patients in the hospital recognize that there are often medical interventions that are done in the pursuit of a diagnosis, of a change in clinical status, that in and of themselves can lead to harm,” Atmar said.

Clinicians likely will have to encourage their patients of all ages to receive second doses of COVID-19 vaccines, despite the malaise they may provoke.

“We really need to make patients aware that this is not going to be a walk in the park. I mean, they’re going to know they had a vaccine, they’re probably not going to feel wonderful, but they’ve got to come back for that second dose,” said Sandra Adamson Fryhofer, MD, who represented the American Medical Association.

ACIP is expected to meet again to offer specific recommendations on the Pfizer and Moderna vaccines. ACIP’s recommendations trigger reimbursement processes, Azar said at a Tuesday press conference. ACIP’s work will inform decisions made by the federal government and governors about deploying shipments of COVID-19 vaccines, he said.

“At the end of the day, that is a decision, though, of the US government to make, which is where to recommend the prioritization,” Azar said. “It will be our nation’s governors in implementing the distribution plans to tell us” where to ship the vaccine.

This article first appeared on Medscape.com.

On Monday, members of an influential federal panel delved into the challenges ahead in deciding who will get the first doses of COVID-19 vaccines, including questions about which healthcare workers need those initial vaccinations the most.

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) did not take any votes or seek to establish formal positions. Instead, the meeting served as a forum for experts to discuss the thorny issues ahead. The US Food and Drug Administration (FDA) could make a decision next month regarding clearance for the first COVID-19 vaccine.

An FDA advisory committee will meet December 10 to review the request for emergency use authorization (EUA) of a COVID-19 vaccine from Pfizer, in partnership with BioNTech. Moderna Inc said on November 16 that it expects to soon ask the FDA for an EUA of its rival COVID vaccine.

ACIP will face a two-part task after the FDA clears COVID-19 vaccines, said Nancy Messonnier, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases. ACIP will need to first decide whether to recommend use of the vaccine and then address the “complicated and difficult” question of which groups should get the initial limited quantities.

“There aren’t any perfect decisions,” she told the ACIP members. “I know this is something that most of you didn’t anticipate doing, making these kinds of huge decisions in the midst of a pandemic.”

There has been considerable public discussion of prioritization of COVID-19 vaccines, including a set of recommendations offered by a special committee created by the National Academies of Sciences, Engineering and Medicine. In addition, CDC staff and members of ACIP outlined what they termed the “four ethical principles” meant to guide these decisions in a November 23 report in the agency’s Morbidity and Mortality Weekly Report. These four principles are to maximize benefits and minimize harms; promote justice; mitigate health inequities; and promote transparency.

But as the issuing of the first EUA nears, it falls to ACIP to move beyond endorsing broad goals. The panel will need to make decisions as to which groups will have to wait for COVID-19 vaccines.

ACIP members on Monday delved into these kinds of more detailed questions, using a proposed three-stage model as a discussion point.

In phase 1a of this model, healthcare workers and residents of long-term care facilities would be the first people to be vaccinated. Phase 1b would include those deemed essential workers, including police officers, firefighters, and those in education, transportation, food, and agriculture sectors. Phase 1c would include adults with high-risk medical conditions and those aged 65 years and older.

ACIP member Grace M. Lee, MD, MPH, of Stanford University, Stanford, California, questioned whether healthcare workers who are not seeing patients in person should wait to get the vaccines. There has been a marked rise in the use of telehealth during the pandemic, which has spared some clinicians from in-person COVID-19 patient visits in their practices.

“Close partnership with our public health colleagues will be critically important to make sure that we are not trying to vaccinate 100% of our healthcare workforce, if some proportion of our workforce can work from home,” Lee said.

ACIP member Pablo Sánchez, MD, of the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, concurred. Some clinicians, he noted, may have better access to personal protective equipment than others, he said.

“Unfortunately, not all healthcare workers are equal in terms of risk,” Sánchez said. “Within institutions, we’re going to have to prioritize which ones will get” the vaccine.

Clinicians may also make judgments about their own risk and need for early access to COVID-19 vaccinations, Sánchez said.

“I’m 66, and I’d rather give it to somebody much older and sicker than me,” he said.
 

Broader access

Fairly large populations will essentially be competing for limited doses of the first vaccines to reach the market.

The overlap is significant in the four priority groups put forward by CDC. The CDC staff estimated that about 21 million people would fall into the healthcare personnel category, which includes hospital staff, pharmacists, and those working in long-term care facilities. There are about 87 million people in the essential workers groups. More than 100 million adults in the United States, such as those with diabetes and cancers, fall into the high-risk medical conditions group. Another 53 million people are aged 65 and older.

Department of Health and Human Services Secretary Alex Azar on November 18 said the federal government expects to have about 40 million doses of these two vaccines by the end of December, which is enough to provide the two-dose regimen for about 20 million. If all goes as expected, Pfizer and Moderna will ramp up production.

Moderna has said that it expects by the end of this year to have approximately 20 million doses of its vaccine ready to ship in the United States and that it is on track to manufacture 500 million to 1 billion doses globally in 2021. Pfizer and BioNTech have said they expect to produce globally up to 50 million doses in 2020 and up to 1.3 billion doses by the end of 2021.

At the Monday meeting, several ACIP panelists stressed the need to ensure that essential workers get early doses of vaccines.

In many cases, these workers serve in jobs with significant public interaction and live in poor communities. They put themselves and their families at risk. Many of them lack the resources to take precautions available to those better able to isolate, said ACIP member Beth Bell, MD, MPH, of the University of Washington, Seattle, Washington.

“These essential workers are out there putting themselves at risk to allow the rest of us to socially distance,” she said. “Recognizing that not all of them may want to be vaccinated at this stage, we need to provide them with the opportunity early on in the process.”

In Bell’s view, the initial rollout of COVID-19 vaccines will send an important message about sharing this resource.

“If we’re serious about valuing equity, we need to have that baked in early on in the vaccination program,” she said.

Bell also said she was in favor of including people living in nursing homes in the initial wave of vaccinations. Concerns were raised about the frailty of this population.

“Given the mortality impact on the healthcare system from the number of nursing home residents that have been dying, I think on balance it makes sense to include them in phase 1a,” Bell said.

Other ACIP panelists said missteps with early vaccination of people in nursing homes could undermine faith in the treatments. Because of the ages and medical conditions of people in nursing homes, many of them may die after receiving the COVID-19 vaccine. Such deaths would not be associated with vaccine, but the medical community would not yet have evidence to disprove a connection.

There could be a backlash, with people falsely linking the death of a grandparent to the vaccine.

Fellow ACIP member Robert L. Atmar, MD, Baylor College of Medicine, Houston, Texas, was among those who had raised concerns about including people living in long-term care facilities in phase 1a. He said there are not yet enough data to judge the balance of benefits and harms of vaccination for this population.

The Pfizer and Moderna vaccines are “reactagenic,” meaning people may not feel well in the days after receiving the shots. The symptoms could lead to additional health evaluations of older people in nursing homes as clinicians try to figure out whether the patient’s reactions to the vaccine are caused by some condition or infection, Atmar said.

“Those of us who see these patients in the hospital recognize that there are often medical interventions that are done in the pursuit of a diagnosis, of a change in clinical status, that in and of themselves can lead to harm,” Atmar said.

Clinicians likely will have to encourage their patients of all ages to receive second doses of COVID-19 vaccines, despite the malaise they may provoke.

“We really need to make patients aware that this is not going to be a walk in the park. I mean, they’re going to know they had a vaccine, they’re probably not going to feel wonderful, but they’ve got to come back for that second dose,” said Sandra Adamson Fryhofer, MD, who represented the American Medical Association.

ACIP is expected to meet again to offer specific recommendations on the Pfizer and Moderna vaccines. ACIP’s recommendations trigger reimbursement processes, Azar said at a Tuesday press conference. ACIP’s work will inform decisions made by the federal government and governors about deploying shipments of COVID-19 vaccines, he said.

“At the end of the day, that is a decision, though, of the US government to make, which is where to recommend the prioritization,” Azar said. “It will be our nation’s governors in implementing the distribution plans to tell us” where to ship the vaccine.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

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

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

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

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

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

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

Contrary to historical evidence, among older people, elevated LDL cholesterol levels increase risk for heart attack and cardiovascular disease, and older patients benefit as much, if not more, from statins and other cholesterol-lowering drugs than do younger people, two new studies show.

“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.

“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.

“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).

The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.

“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.

“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
 

No RCTs have included patients older than 70

For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.

However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.

Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.

As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
 

Primary prevention: CV events increase with elevated LDL cholesterol in older age

Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.

Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.

Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.

In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).

Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.

Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).

The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.

“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.

With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.

With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.

“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”

“These robust findings are novel,” he and his colleagues stressed.

Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.

The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
 

Unequivocal reductions in events in elderly, comparable with younger patients

In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.

The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.

The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.

The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).

Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).

“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.

“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.

“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”

The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”

The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.

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

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

One month of dual-antiplatelet therapy followed by aspirin monotherapy in patients who’ve received a drug-eluting stent proved noninferior to 6-12 months of DAPT for a composite 1-year endpoint of cardiovascular events or major bleeding in the large, randomized One-Month DAPT trial.

Svisio/Thinkstock

This is the first test of such a strategy. Other trials of short-course DAPT, such as the successful TWILIGHT trial, have dropped the aspirin and continued the P2Y12 inhibitor. But aspirin monotherapy after a single month of DAPT is an attractive alternative in patients undergoing PCI for noncomplex lesions, Myeong-Ki Hong, MD, PhD, said in presenting his results at the American Heart Association scientific sessions.

“In everyday clinical practice, people receiving P2Y12 receptor blockers usually complain of several episodes of minor bleeding. And the cost. Those are strong factors in patient noncompliance,” he said, adding, “I think aspirin monotherapy is more comfortable for the physician and the patient.”

The One-Month DAPT trial included 3,020 patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) at 23 Korean centers. They were split roughly 60/40 between patients with stable angina and those with acute coronary syndrome involving unstable angina. Patients with complex coronary lesions or acute MI were not eligible for enrollment. Participants were randomized to receive either the polymer-free drug-coated BioFreedom stent, in which case they got 1 month of DAPT followed by 11 months of aspirin antiplatelet monotherapy, or they received 6 or 12 months of DAPT in conjunction with a thick-strut BioMatrix or an Ultimaster polymer-based DES. The reason for using different stents in the two study arms is that only the polymer-free stent completes drug release within 1 month; other contemporary DESs release their drug for 3-4 months, and it’s risky to discontinue one of the antiplatelet agents during drug elution, said Dr. Hong, professor of cardiology at Yonsei University in Seoul, South Korea.
 

Patients with stable angina fared best

The primary endpoint in this noninferiority trial was the 1-year composite of cardiac death, MI, target vessel revascularization, stroke, or major bleeding. The incidence was 5.9% in the 1-month DAPT group, statistically noninferior to the 6.5% figure in the 6- or 12-month DAPT group. The major bleeding rate at 1 year was 1.7% with 1 month of DAPT and 2.5% with 6-12 months of DAPT, a nonsignificant difference. Of note, the primary composite endpoint occurred in 5.1% of patients with stable angina who were randomized to 1 month of DAPT, compared with 7.6% with 6 or 12 months of DAPT, a statistically significant difference that translated into a 33% relative risk reduction. In contrast, in patients with unstable angina the primary endpoint occurred in 7.2% of those on 1 month of DAPT and 5.1% with 6 or 12 months of DAPT, a trend that didn’t reach significance.

Roughly 75% of patients in the long-DAPT arm were assigned to 12 months of DAPT. That’s because the trial began in 2015, before clinical practice guidelines declared 6 months of DAPT to be the recommendation in patients with stable coronary artery disease. The choice of 6 versus 12 months of DAPT in the trial was left up to the patient’s physician.

Discussant Roisin Colleran, MBBCh, said the study addresses “an unmet clinical need” for improved antiplatelet regimens following PCI with DES.
 

Trial’s shortcomings temper reaction

“After a period of short DAPT, aspirin monotherapy may be preferable to P2Y12 monotherapy because it’s cheaper, with fewer off-target side effects, less variation in treatment response, and fewer contraindications,” said Dr. Colleran, a cardiologist at Mater Private Hospital, Dublin.

That being said, she shared several reservations about the study. For one, none of the three stents used in the trial is approved by the Food and Drug Administration. The results may not be generalizable to non–East Asian populations. The use of 12 months of DAPT in stable angina patients is out of step with current U.S. and European practice guidelines, which recommend 6 months. And 17% of patients in the 1-month DAPT group were noncompliant with that strategy, meaning they continued on DAPT; had that reverse noncompliance rate been lower, the between-group difference in the primary endpoint might have become statistically significant.

Dr. Hong said he thinks the study findings are applicable elsewhere in the world. The 1-month DAPT followed by aspirin monotherapy strategy is attractive in elderly patients, those on oral anticoagulation for atrial fibrillation, individuals who need to undergo noncardiac surgery, and in the large group of stable patients with noncomplex coronary lesions.

“Let’s provide these patients with some options,” the cardiologist urged.

He is particularly keen on the combination of a polymer-free stent with a drug-elution period of less than 1 month.

“Is polymer perfect? I don’t think so. The polymer is a foreign body. It’s fantastic, but in 5 or 10 years the polymer may cause irritation and chronic inflammation and a new lesion,” Dr. Hong said.

Session moderator Wayne B. Batchelor, MD, commented on the battle for stent market share: “It almost appears that we’re getting to a ceiling point with coronary interventions whereby at a year we’re getting such low ischemic event rates – they’re often in the 5%-7% range – that all of these [head-to-head] studies are noninferiority studies, because it’s just the only way to do these comparisons nowadays. We can’t do 10-, 15-, or 20,000-patient trials. But these noninferiority margins are quite broad.”

“Are we stuck just saying: ‘All stents are equal,’ or are we going to be able to get to the point that we can show that a healing stent is superior?” asked Dr. Batchelor, director of interventional cardiology and interventional cardiology research at the Inova Medical Group in Falls Church, Va.

“I think it’s going to be very hard to beat the current technology,” observed panelist Alexandre Abizaid, MD, PhD, of the Dante Pazzanese Institute of Cardiology in São Paulo. “Even though the polymers are durable, they’re biocompatible, and they’re hard to beat. It’s not going to be easy to show superiority. Maybe in patient subsets.”

Dr. Hong reported having no financial conflicts of interest regarding the One-Month DAPT trial, funded by DIO, Cardinal Health Korea, and Terumo.

[email protected]

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

The COVID-19 pandemic has decimated the bottom lines of many private practices, prompting physician-owners to seriously contemplate selling.

Physician-owners have had to sell at lower prices, reflecting lower cash flow under COVID-19. But sales prices may rebound following news on Nov. 9 that a COVID-19 vaccine candidate produced by Pfizer and its German partner, BioNTech, may be ready for initial distribution before the end of the year.

“There are a lot of ifs still, but if things go according to expectations, we may see an increase in the value of practices,” said Mark O. Dietrich, a CPA in Framingham, Mass., who deals mostly with valuations of physician practices.

“Practice valuations have been lower because many patients have kept away and cash flow has been reduced,” Mr. Dietrich said. “But once patients feel safe, that barrier would be removed, and cash flow, which sales prices are generally based on, could rise. However, this may take a while. One major hurdle would be getting people to take the vaccine.”
 

Many doctors have been contemplating closing

The nation is currently undergoing a significant spike in COVID-19 hospitalizations, which could prompt another COVID-19–related downturn in practice volume, as occurred earlier in the year. That downturn forced many private practitioners to contemplate selling their practices.

In a survey released this summer by McKinsey & Company, 53% of independent physicians reported that they were worried about their practices surviving. Although many physicians have now reopened their offices, patient volume is reduced, and physicians are earning far less than before.

“In many cases, physicians who had been considering retirement in the next few years have moved their planning up and want to sell as soon as possible,” said John D. Fanburg, an attorney at Brach Eichler, a law firm in Roseland, N.J., who specializes in medical practice sales and mergers.

“For physicians over age 65, it’s not just worries about finances; it’s also worries about the health risks of staying open,” Mr. Fanburg added.

Mid-career physicians are also selling their practices. Many of them become employees of the hospital, large practice, or private-equity firm that bought the practice – receiving a level of compensation set by the sales agreement.
 

Will your practice be hard to sell?

With so many physicians ready to sell, are there enough potential buyers to acquire them all? Probably not, said Mr. Dietrich.

“Many hospitals may not need new practices right now,” he said. “In the depths of the pandemic, they furloughed many of their existing doctors and may not have brought all of them back yet.”

In fact, because of the pandemic, some buyers have delayed sales that were already in progress, said Monica H. Kaden, director of business valuations at Sobel Valuations, based in Livingston, N.J.

“Buyers are not only worried about their own cash flow but also about the possibility of lower revenues of the selling practices due to COVID-19,” she said, citing a very large multispecialty group that has put its purchase of a another large multispecialty group on hold.
 

Practice values have (temporarily) fallen

Many potential buyers are still looking, though. One thing that drives them is the possibility of discounted sales because of COVID-19. “The sense I get is that a lot of hospitals see this as an opportunity to pick up practices on the cheap,” Mr. Dietrich said.

COVID-19 has been reducing practice values somewhat, said Reed Tinsley, a CPA in Houston who performs medical practice valuations and runs a practice brokerage firm. “Practice revenues and net income are lower under COVID-19, so prices are lower.”

Ms. Kadan advised physicians to hold off selling if they can afford to wait. “It’s always best to sell when the practice volume looks the best, because then the practice is worth more. But there are doctors who can’t wait because revenues are really falling and they are running out of money. They may have no choice but to sell.”

Even in the best of times, not all practices can be sold, said Sean Tinsley, a broker and licensed financial adviser at Tinsley Medical Practice Brokers in Austin, Tex., which he runs with his father, Reed Tinsley.

“We turn down about as many deals to sell practices as we accept,” he said. “Brokers have to be very selective because we don’t get paid until the practice gets sold. Generally, we won’t take practices in rural areas or practices that still only have a fraction of their pre–COVID-19 volume.”
 

How long will it take to sell your practice?

Some practices find a buyer within weeks, but in other cases, it can take as long as a year, he said. Once the buyer is located, preparing the paperwork for the sale can take 45-60 days.

Doctors can sell their practices on their own, but a broker can help them find potential buyers and select the right price. Business brokers generally receive a greater percentage of the sales price than residential brokers. They have greater command of business and finance, and the sale is more complex than a residential sale.

The broker may also help with selling the building where the practice is located, which is usually a separate sale, said Bruce E. Wood, an attorney at CCB Law in Syracuse, N.Y., who deals with practice sales. “A hospital buying your practice may not want to buy the building, so it has to be sold separately. You can always sell the space to a different buyer.”
 

What’s the right price for your practice?

For small practices, brokers often set a price by establishing a multiple, such as two times net earnings, Sean Tinsley said. In many cases, practices haven’t retained net earnings, so the broker uses gross annual revenue and sets the price at 50%-55% of that figure.

An alternative that is widely used in the business world and for many large practices is to base the price on earnings before interest, taxes, depreciation, and amortization (EBITDA). To determine a price, the EBITDA is then multiplied by a particular multiple, which depends on the perceived value of the practice.

Higher multiples go to practices that have a qualified management team, have documented financial policies and procedures, or have had significant past growth. Generally, the multiple of EBITDA at smaller practices is 1 or 2; larger practices have a multiple of 5-7 times EBITDA, Sean Tinsley said.

COVID-19 has had the effect of reducing the multiple somewhat. “As market forces shift from a seller’s market to a buyer’s market, multiples will likely remain below pre–COVID-19 levels for the remainder of 2020 and the first half of 2021,” one report stated.

Certified valuators like Reed Tinsley have more complex ways to establish the value of a practice, but as a broker, Sean Tinsley tends to use the multiples approach. He asserted that the prices derived from this method are on the mark. “Almost all the time we sell at the asking price.”
 

Using valuations to set the price

A more complex and expensive way to set a price for a practice is to order a valuation of the practice. The valuator issues a report that runs dozens of pages and costs thousands of dollars.

Mr. Fanburg said that very few physicians selling practices order valuation reports, owing to the cost and complexity. As a result, “they don’t have a clear idea what their practices are worth.”

A comprehensive report is called a conclusion of value. The amount it finds – expressed as a range – is called “fair market value.” The report can be used in the courts for legal disputes as well as for deriving a sales price.

Practices that don’t want to pay for a conclusion of value can ask a valuator to assemble a less extensive report, called an opinion of calculated value. Also known as a calculation engagement or engagement letter, it still costs several thousand dollars.

This report has limited validity and can’t be used in the courts, according to Jarrod Barraza, a certified valuator in the Nashville, Tenn., office of Horne, a health care business valuator. “When I issue an engagement letter, I am not talking as an appraiser but as a valuation consultant, and I don’t call the result fair market value; it’s only estimating,” he said.

For all of the precision of formal reports, however, valuations of a practice can vary widely, according to Reed Tinsley. “Two valuations using the same methodology can differ by $300,000.”

Also, the valuation can be well above a reasonable asking price, said Sean Tinsley. “The market dictates the price. A traditional valuation almost invariably quotes a higher return than the market is willing to pay.”
 

Buyers’ valuations

Physicians who decide not to get a valuation still have to deal with valuations ordered by buyers. Hospitals and large practices often order valuations of the practices they want to buy, and private-equity firms use methods much like a valuation for the practices they are interested in.

Buyers rarely share the valuation report with the seller, so the seller has to accept the buyer’s price without being able to review the thought process behind it, Mr. Fanburg said. “Relying on the buyer to tell you what you’re worth means you may sell your practice well below its true value.”

When the buyer orders a valuation, the valuator interviews managers of the practice and asks for a great deal of information, says G. Don Barbo, managing director at VMG Health, a health care valuation firm based in Dallas.

Mr. Barbo said these documents include financial statements for the practice, usually going back 3-5 years; productivity reports for doctors and other providers; accounts receivables; reports of fixed assets; a roster of employees; employment agreements and management services agreements; reports on payer mix; facility leases and equipment lease agreements; budgets and projections; and tax returns.

Mr. Dietrich said valuators hone in on the practice’s current procedural terminology codes. “If the practice is coding too high, this would artificially increase the profit and purported value of the practice. For example, coding at 99214 rather than 99213 for an established patient means that the practice is being paid 45% more for each visit.” The valuator then reduces the value of the practice on the basis of the extent of the improper up-coding.

Mr. Barbo said some sellers don’t want all the scrutiny of the buyer’s valuation and just sell the practice’s tangible assets – furnishings, fixtures, and equipment – which do not require a great deal of documentation but yield a much lower price.
 

A primer on valuations

As a valuator, “my job is to project into the future,” Mr. Barraza said. “I am trying to see how the practice will fare going forward.”

Mr. Dietrich agreed, with one caveat: “As Yogi Berra said: ‘It’s difficult to make predictions, especially about the future.’ ”

The formal valuation assesses the practice in three ways: measuring income, assets, and what other practices sell for, called the market approach.

With the income approach, the most used measurement for practices, one tries to determine future income, which is what buyers are most interested in, Mr. Dietrich said. The income equals revenue (total collections) minus operating expenses and overhead.

“You are then left with all the money the physician is paid,” he said. “The issue is, how much is attributed to the physician’s own labor and how much to his or her ownership of the practice? This second category helps determine the value of the practice.”

The market approach is often used as a way to double-check the accuracy of the income approach. The appraiser looks for the prices of similar practices that have already been sold and then adjusts the price on the basis of differences with the practice up for sale.

The asset approach may be used when the practice has no positive cash flow. It establishes a price for tangible assets, which are often much lower in value than the values that the other approaches come up with. The asset approach can be a lower-priced alternative for practices that can’t be measured under the income or market approach.

“Equipment appraisers can do an inventory of your equipment,” Mr. Wood said. “Generally, equipment that is more than 3 years old, such as computers, is not that valuable, but an ultrasound machine probably has some resale value.”
 

Will the buyer pay for goodwill?

Many practice owners hope they can get money for the “goodwill” of their practice when they sell. Goodwill basically represents the reputation of the practice, which is difficult to pinpoint, and Mr. Wood said buyers often don’t want to pay for it.

“The goodwill is a wild card,” Mr. Wood said. “It can range from zero to crazy numbers. There is a Goodwill Registry – a list of the goodwill in other practice sales – that you can consult.”

One simple way to calculate the goodwill, he said, is to take the value of the practice based on examining income and remove the value of tangible assets. What is left is considered the goodwill.

Another form of intangible asset that is sometimes lumped together with goodwill is the value of the practice’s trained staff. “Some buyers agree to pay for the staff in place, because they plan to use that staff,” Ms. Kadan said. In one large deal she was involved with, the buyer agreed to pay something for the selling practice’s staff of 180 people.

Another item that buyers also do not typically pay for is the practice’s accounts receivable. They may also not pay for any liabilities the practice holds, such as the facility lease, equipment lease, and maintenance contracts, Mr. Barbo said. “The buyer then often stipulates that all liabilities are left to the practice, or stipulates any specific liabilities that it may assume.”
 

Selling to other doctors

Doctors can sell practices or shares in practices to other doctors. A retiring physician, for example, can sell his or her share to the other partners. A valuator may be brought in to establish the value of the doctor’s equity interest in the practice.

“Generally, practice buyouts aren’t lucrative for selling physician,” Mr. Wood said. “There are exceptions, of course, such as specialty practices in some cases.”

A practice can also be sold to a new doctor or to a previously employed physician who wants to be an owner. These physicians usually need to get a bank loan to buy the practice.

The bank assesses the finances of the selling practice to determine whether the buying physician will earn enough money to pay back the loan. “Banks don’t want lend more than the gross annual revenue of the practice, and some banks will only lend at 65% of gross annual revenue,” Sean Tinsley said.

COVID-19 has seriously affected banks’ lending decisions. Banks stopped lending to practice buyers at the beginning of the pandemic, and when they started lending again, they were more cautious, Sean Tinsley said. “Generally, banks want to see the practice at 85%-90% of pre–COVID-19 numbers before they make a loan.”

He added that, if a buyer can’t get a bank loan, the selling doctor may decide to finance the sale. The buyer agrees to a payment schedule to pay off the full price over several years.
 

Selling to or merging with other practices

The usual buyer is another practice, Reed Tinsley said. “You can sell to a group, but prices are low because, with COVID-19, buyers don’t want to incur a lot of money up front. Or you can merge with the practice, which means the selling doctor usually doesn’t get any money, but he does get a share in the larger practice. In that case, the partnership is the object of value, and it can be cashed out when the physician leaves the practice.”

Mergers can get very complicated. Mr. Fanburg said he has been working with seven groups that are merging into one. “The merger was scheduled to go live last January, but it was slowed down over negotiations about new managed care contracts and putting together a management structure, plus the groups were a little wary of each other. Now the deal is scheduled to go live next January.”

One advantage to selling to a larger entity, such as a big group practice or a hospital, is that the selling physician benefits from the higher reimbursement rates that large providers usually command. “If the buyer has more favorable reimbursement rates with insurers, it could pay the selling doctor much more than he is making now,” Mr. Barraza said.
 

Hospitals as buyers

Because of COVID-19, currently many hospitals don’t have money to buy more practices. However, this is most likely a temporary situation.

Hospitals typically offer less money than other buyers, according to Sean Tinsley. “We have never sold to a hospital, because hospitals generally don’t pay for goodwill. They pay for the practice assets and offer a dollar amount for each chart.”

Hospitals have to be careful not to pay physicians more than the usual amount for their practices, because the extra amount could be seen as a kickback for referrals, which would violate the federal Stark law and Anti-Kickback Statute. Not-for-profit hospitals also have to comply with regulations at the Internal Revenue Service.

Hospitals usually require that the selling physician continue to work in the practice after it is sold. The selling physician’s presence helps ensure that the practice’s output will not decline after sale. Although the sales price may be low, the hospital may make up for it by paying a higher compensation, Sean Tinsley said.
 

Selling to private-equity firms

Private-equity purchases are financed by investors who essentially want to “flip” practices – that is, they want to make them more profitable and then sell them to someone else. The private-equity firm starts by buying a “platform” practice, which forms the core of the venture. It then buys smaller practices that will be managed by the platform practice.

The number of private-equity deals increased continually through 2019, then plummeted in March because of COVID-19, but by the summer, activity began to rise again.

Physicians are very intrigued about selling to private-equity firms because they are known to pay the most for practices. But private-equity buyers focus on a fairly narrow group of specialties.

Generally, Sean Tinsley said, private-equity firms only look for pain, dermatology, and ophthalmology practices, but they have been starting to branch out to specialties such as gastroenterology. In 2018, there were only two private-equity deals for gastroenterology practices, but in 2019, there were 16, according to one assessment.

Private-equity firms buy very few of the practices they initially review, according to Mr. Fanburg. “Private equity negotiates with dozens or even hundreds of physician practices at a time, with only 1%-5% of those practices actually being acquired.”

The private-equity firm’s upfront payment to selling physicians is quite high, but then the physicians become employees of the new group and earn much less in compensation than they earned on this own.

“In order for the venture to get any value out of the acquisition, the doctors have to make less going forward than they did historically,” Mr. Dietrich said. That freed-up money boosts the value of the venture.

When the platform practice is sold – usually after 5 years or so – “chances are the management team will be replaced,” Mr. Fanburg said. “There could be new policies and objectives, which could mean a bumpy ride for physicians.”
 

Do you really want to sell?

“When a group of physicians comes to me asking for help selling their practice, my first question is, Why are you doing this?” Mr. Fanburg said. “You need a better reason for selling than just the money.

“Once you make the leap, there is a certain amount of autonomy you lose,” he continued. “The sale gives you an economic boost, but it may not be enough for the long haul. If you stay on with the buyer, your compensation is often lower. That makes sense if you’re retiring, but not if you’re a younger physician with many years of practice in the years ahead.

“When physicians say they see no other way out except to sell,” Mr. Fanburg said, “I tell them that their buyer will see a path to future growth for your practice. If you think reimbursements are getting worse, why are the buyers pressing ahead?”

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

The COVID-19 pandemic has decimated the bottom lines of many private practices, prompting physician-owners to seriously contemplate selling.

Physician-owners have had to sell at lower prices, reflecting lower cash flow under COVID-19. But sales prices may rebound following news on Nov. 9 that a COVID-19 vaccine candidate produced by Pfizer and its German partner, BioNTech, may be ready for initial distribution before the end of the year.

“There are a lot of ifs still, but if things go according to expectations, we may see an increase in the value of practices,” said Mark O. Dietrich, a CPA in Framingham, Mass., who deals mostly with valuations of physician practices.

“Practice valuations have been lower because many patients have kept away and cash flow has been reduced,” Mr. Dietrich said. “But once patients feel safe, that barrier would be removed, and cash flow, which sales prices are generally based on, could rise. However, this may take a while. One major hurdle would be getting people to take the vaccine.”
 

Many doctors have been contemplating closing

The nation is currently undergoing a significant spike in COVID-19 hospitalizations, which could prompt another COVID-19–related downturn in practice volume, as occurred earlier in the year. That downturn forced many private practitioners to contemplate selling their practices.

In a survey released this summer by McKinsey & Company, 53% of independent physicians reported that they were worried about their practices surviving. Although many physicians have now reopened their offices, patient volume is reduced, and physicians are earning far less than before.

“In many cases, physicians who had been considering retirement in the next few years have moved their planning up and want to sell as soon as possible,” said John D. Fanburg, an attorney at Brach Eichler, a law firm in Roseland, N.J., who specializes in medical practice sales and mergers.

“For physicians over age 65, it’s not just worries about finances; it’s also worries about the health risks of staying open,” Mr. Fanburg added.

Mid-career physicians are also selling their practices. Many of them become employees of the hospital, large practice, or private-equity firm that bought the practice – receiving a level of compensation set by the sales agreement.
 

Will your practice be hard to sell?

With so many physicians ready to sell, are there enough potential buyers to acquire them all? Probably not, said Mr. Dietrich.

“Many hospitals may not need new practices right now,” he said. “In the depths of the pandemic, they furloughed many of their existing doctors and may not have brought all of them back yet.”

In fact, because of the pandemic, some buyers have delayed sales that were already in progress, said Monica H. Kaden, director of business valuations at Sobel Valuations, based in Livingston, N.J.

“Buyers are not only worried about their own cash flow but also about the possibility of lower revenues of the selling practices due to COVID-19,” she said, citing a very large multispecialty group that has put its purchase of a another large multispecialty group on hold.
 

Practice values have (temporarily) fallen

Many potential buyers are still looking, though. One thing that drives them is the possibility of discounted sales because of COVID-19. “The sense I get is that a lot of hospitals see this as an opportunity to pick up practices on the cheap,” Mr. Dietrich said.

COVID-19 has been reducing practice values somewhat, said Reed Tinsley, a CPA in Houston who performs medical practice valuations and runs a practice brokerage firm. “Practice revenues and net income are lower under COVID-19, so prices are lower.”

Ms. Kadan advised physicians to hold off selling if they can afford to wait. “It’s always best to sell when the practice volume looks the best, because then the practice is worth more. But there are doctors who can’t wait because revenues are really falling and they are running out of money. They may have no choice but to sell.”

Even in the best of times, not all practices can be sold, said Sean Tinsley, a broker and licensed financial adviser at Tinsley Medical Practice Brokers in Austin, Tex., which he runs with his father, Reed Tinsley.

“We turn down about as many deals to sell practices as we accept,” he said. “Brokers have to be very selective because we don’t get paid until the practice gets sold. Generally, we won’t take practices in rural areas or practices that still only have a fraction of their pre–COVID-19 volume.”
 

How long will it take to sell your practice?

Some practices find a buyer within weeks, but in other cases, it can take as long as a year, he said. Once the buyer is located, preparing the paperwork for the sale can take 45-60 days.

Doctors can sell their practices on their own, but a broker can help them find potential buyers and select the right price. Business brokers generally receive a greater percentage of the sales price than residential brokers. They have greater command of business and finance, and the sale is more complex than a residential sale.

The broker may also help with selling the building where the practice is located, which is usually a separate sale, said Bruce E. Wood, an attorney at CCB Law in Syracuse, N.Y., who deals with practice sales. “A hospital buying your practice may not want to buy the building, so it has to be sold separately. You can always sell the space to a different buyer.”
 

What’s the right price for your practice?

For small practices, brokers often set a price by establishing a multiple, such as two times net earnings, Sean Tinsley said. In many cases, practices haven’t retained net earnings, so the broker uses gross annual revenue and sets the price at 50%-55% of that figure.

An alternative that is widely used in the business world and for many large practices is to base the price on earnings before interest, taxes, depreciation, and amortization (EBITDA). To determine a price, the EBITDA is then multiplied by a particular multiple, which depends on the perceived value of the practice.

Higher multiples go to practices that have a qualified management team, have documented financial policies and procedures, or have had significant past growth. Generally, the multiple of EBITDA at smaller practices is 1 or 2; larger practices have a multiple of 5-7 times EBITDA, Sean Tinsley said.

COVID-19 has had the effect of reducing the multiple somewhat. “As market forces shift from a seller’s market to a buyer’s market, multiples will likely remain below pre–COVID-19 levels for the remainder of 2020 and the first half of 2021,” one report stated.

Certified valuators like Reed Tinsley have more complex ways to establish the value of a practice, but as a broker, Sean Tinsley tends to use the multiples approach. He asserted that the prices derived from this method are on the mark. “Almost all the time we sell at the asking price.”
 

Using valuations to set the price

A more complex and expensive way to set a price for a practice is to order a valuation of the practice. The valuator issues a report that runs dozens of pages and costs thousands of dollars.

Mr. Fanburg said that very few physicians selling practices order valuation reports, owing to the cost and complexity. As a result, “they don’t have a clear idea what their practices are worth.”

A comprehensive report is called a conclusion of value. The amount it finds – expressed as a range – is called “fair market value.” The report can be used in the courts for legal disputes as well as for deriving a sales price.

Practices that don’t want to pay for a conclusion of value can ask a valuator to assemble a less extensive report, called an opinion of calculated value. Also known as a calculation engagement or engagement letter, it still costs several thousand dollars.

This report has limited validity and can’t be used in the courts, according to Jarrod Barraza, a certified valuator in the Nashville, Tenn., office of Horne, a health care business valuator. “When I issue an engagement letter, I am not talking as an appraiser but as a valuation consultant, and I don’t call the result fair market value; it’s only estimating,” he said.

For all of the precision of formal reports, however, valuations of a practice can vary widely, according to Reed Tinsley. “Two valuations using the same methodology can differ by $300,000.”

Also, the valuation can be well above a reasonable asking price, said Sean Tinsley. “The market dictates the price. A traditional valuation almost invariably quotes a higher return than the market is willing to pay.”
 

Buyers’ valuations

Physicians who decide not to get a valuation still have to deal with valuations ordered by buyers. Hospitals and large practices often order valuations of the practices they want to buy, and private-equity firms use methods much like a valuation for the practices they are interested in.

Buyers rarely share the valuation report with the seller, so the seller has to accept the buyer’s price without being able to review the thought process behind it, Mr. Fanburg said. “Relying on the buyer to tell you what you’re worth means you may sell your practice well below its true value.”

When the buyer orders a valuation, the valuator interviews managers of the practice and asks for a great deal of information, says G. Don Barbo, managing director at VMG Health, a health care valuation firm based in Dallas.

Mr. Barbo said these documents include financial statements for the practice, usually going back 3-5 years; productivity reports for doctors and other providers; accounts receivables; reports of fixed assets; a roster of employees; employment agreements and management services agreements; reports on payer mix; facility leases and equipment lease agreements; budgets and projections; and tax returns.

Mr. Dietrich said valuators hone in on the practice’s current procedural terminology codes. “If the practice is coding too high, this would artificially increase the profit and purported value of the practice. For example, coding at 99214 rather than 99213 for an established patient means that the practice is being paid 45% more for each visit.” The valuator then reduces the value of the practice on the basis of the extent of the improper up-coding.

Mr. Barbo said some sellers don’t want all the scrutiny of the buyer’s valuation and just sell the practice’s tangible assets – furnishings, fixtures, and equipment – which do not require a great deal of documentation but yield a much lower price.
 

A primer on valuations

As a valuator, “my job is to project into the future,” Mr. Barraza said. “I am trying to see how the practice will fare going forward.”

Mr. Dietrich agreed, with one caveat: “As Yogi Berra said: ‘It’s difficult to make predictions, especially about the future.’ ”

The formal valuation assesses the practice in three ways: measuring income, assets, and what other practices sell for, called the market approach.

With the income approach, the most used measurement for practices, one tries to determine future income, which is what buyers are most interested in, Mr. Dietrich said. The income equals revenue (total collections) minus operating expenses and overhead.

“You are then left with all the money the physician is paid,” he said. “The issue is, how much is attributed to the physician’s own labor and how much to his or her ownership of the practice? This second category helps determine the value of the practice.”

The market approach is often used as a way to double-check the accuracy of the income approach. The appraiser looks for the prices of similar practices that have already been sold and then adjusts the price on the basis of differences with the practice up for sale.

The asset approach may be used when the practice has no positive cash flow. It establishes a price for tangible assets, which are often much lower in value than the values that the other approaches come up with. The asset approach can be a lower-priced alternative for practices that can’t be measured under the income or market approach.

“Equipment appraisers can do an inventory of your equipment,” Mr. Wood said. “Generally, equipment that is more than 3 years old, such as computers, is not that valuable, but an ultrasound machine probably has some resale value.”
 

Will the buyer pay for goodwill?

Many practice owners hope they can get money for the “goodwill” of their practice when they sell. Goodwill basically represents the reputation of the practice, which is difficult to pinpoint, and Mr. Wood said buyers often don’t want to pay for it.

“The goodwill is a wild card,” Mr. Wood said. “It can range from zero to crazy numbers. There is a Goodwill Registry – a list of the goodwill in other practice sales – that you can consult.”

One simple way to calculate the goodwill, he said, is to take the value of the practice based on examining income and remove the value of tangible assets. What is left is considered the goodwill.

Another form of intangible asset that is sometimes lumped together with goodwill is the value of the practice’s trained staff. “Some buyers agree to pay for the staff in place, because they plan to use that staff,” Ms. Kadan said. In one large deal she was involved with, the buyer agreed to pay something for the selling practice’s staff of 180 people.

Another item that buyers also do not typically pay for is the practice’s accounts receivable. They may also not pay for any liabilities the practice holds, such as the facility lease, equipment lease, and maintenance contracts, Mr. Barbo said. “The buyer then often stipulates that all liabilities are left to the practice, or stipulates any specific liabilities that it may assume.”
 

Selling to other doctors

Doctors can sell practices or shares in practices to other doctors. A retiring physician, for example, can sell his or her share to the other partners. A valuator may be brought in to establish the value of the doctor’s equity interest in the practice.

“Generally, practice buyouts aren’t lucrative for selling physician,” Mr. Wood said. “There are exceptions, of course, such as specialty practices in some cases.”

A practice can also be sold to a new doctor or to a previously employed physician who wants to be an owner. These physicians usually need to get a bank loan to buy the practice.

The bank assesses the finances of the selling practice to determine whether the buying physician will earn enough money to pay back the loan. “Banks don’t want lend more than the gross annual revenue of the practice, and some banks will only lend at 65% of gross annual revenue,” Sean Tinsley said.

COVID-19 has seriously affected banks’ lending decisions. Banks stopped lending to practice buyers at the beginning of the pandemic, and when they started lending again, they were more cautious, Sean Tinsley said. “Generally, banks want to see the practice at 85%-90% of pre–COVID-19 numbers before they make a loan.”

He added that, if a buyer can’t get a bank loan, the selling doctor may decide to finance the sale. The buyer agrees to a payment schedule to pay off the full price over several years.
 

Selling to or merging with other practices

The usual buyer is another practice, Reed Tinsley said. “You can sell to a group, but prices are low because, with COVID-19, buyers don’t want to incur a lot of money up front. Or you can merge with the practice, which means the selling doctor usually doesn’t get any money, but he does get a share in the larger practice. In that case, the partnership is the object of value, and it can be cashed out when the physician leaves the practice.”

Mergers can get very complicated. Mr. Fanburg said he has been working with seven groups that are merging into one. “The merger was scheduled to go live last January, but it was slowed down over negotiations about new managed care contracts and putting together a management structure, plus the groups were a little wary of each other. Now the deal is scheduled to go live next January.”

One advantage to selling to a larger entity, such as a big group practice or a hospital, is that the selling physician benefits from the higher reimbursement rates that large providers usually command. “If the buyer has more favorable reimbursement rates with insurers, it could pay the selling doctor much more than he is making now,” Mr. Barraza said.
 

Hospitals as buyers

Because of COVID-19, currently many hospitals don’t have money to buy more practices. However, this is most likely a temporary situation.

Hospitals typically offer less money than other buyers, according to Sean Tinsley. “We have never sold to a hospital, because hospitals generally don’t pay for goodwill. They pay for the practice assets and offer a dollar amount for each chart.”

Hospitals have to be careful not to pay physicians more than the usual amount for their practices, because the extra amount could be seen as a kickback for referrals, which would violate the federal Stark law and Anti-Kickback Statute. Not-for-profit hospitals also have to comply with regulations at the Internal Revenue Service.

Hospitals usually require that the selling physician continue to work in the practice after it is sold. The selling physician’s presence helps ensure that the practice’s output will not decline after sale. Although the sales price may be low, the hospital may make up for it by paying a higher compensation, Sean Tinsley said.
 

Selling to private-equity firms

Private-equity purchases are financed by investors who essentially want to “flip” practices – that is, they want to make them more profitable and then sell them to someone else. The private-equity firm starts by buying a “platform” practice, which forms the core of the venture. It then buys smaller practices that will be managed by the platform practice.

The number of private-equity deals increased continually through 2019, then plummeted in March because of COVID-19, but by the summer, activity began to rise again.

Physicians are very intrigued about selling to private-equity firms because they are known to pay the most for practices. But private-equity buyers focus on a fairly narrow group of specialties.

Generally, Sean Tinsley said, private-equity firms only look for pain, dermatology, and ophthalmology practices, but they have been starting to branch out to specialties such as gastroenterology. In 2018, there were only two private-equity deals for gastroenterology practices, but in 2019, there were 16, according to one assessment.

Private-equity firms buy very few of the practices they initially review, according to Mr. Fanburg. “Private equity negotiates with dozens or even hundreds of physician practices at a time, with only 1%-5% of those practices actually being acquired.”

The private-equity firm’s upfront payment to selling physicians is quite high, but then the physicians become employees of the new group and earn much less in compensation than they earned on this own.

“In order for the venture to get any value out of the acquisition, the doctors have to make less going forward than they did historically,” Mr. Dietrich said. That freed-up money boosts the value of the venture.

When the platform practice is sold – usually after 5 years or so – “chances are the management team will be replaced,” Mr. Fanburg said. “There could be new policies and objectives, which could mean a bumpy ride for physicians.”
 

Do you really want to sell?

“When a group of physicians comes to me asking for help selling their practice, my first question is, Why are you doing this?” Mr. Fanburg said. “You need a better reason for selling than just the money.

“Once you make the leap, there is a certain amount of autonomy you lose,” he continued. “The sale gives you an economic boost, but it may not be enough for the long haul. If you stay on with the buyer, your compensation is often lower. That makes sense if you’re retiring, but not if you’re a younger physician with many years of practice in the years ahead.

“When physicians say they see no other way out except to sell,” Mr. Fanburg said, “I tell them that their buyer will see a path to future growth for your practice. If you think reimbursements are getting worse, why are the buyers pressing ahead?”

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

The COVID-19 pandemic has decimated the bottom lines of many private practices, prompting physician-owners to seriously contemplate selling.

Physician-owners have had to sell at lower prices, reflecting lower cash flow under COVID-19. But sales prices may rebound following news on Nov. 9 that a COVID-19 vaccine candidate produced by Pfizer and its German partner, BioNTech, may be ready for initial distribution before the end of the year.

“There are a lot of ifs still, but if things go according to expectations, we may see an increase in the value of practices,” said Mark O. Dietrich, a CPA in Framingham, Mass., who deals mostly with valuations of physician practices.

“Practice valuations have been lower because many patients have kept away and cash flow has been reduced,” Mr. Dietrich said. “But once patients feel safe, that barrier would be removed, and cash flow, which sales prices are generally based on, could rise. However, this may take a while. One major hurdle would be getting people to take the vaccine.”
 

Many doctors have been contemplating closing

The nation is currently undergoing a significant spike in COVID-19 hospitalizations, which could prompt another COVID-19–related downturn in practice volume, as occurred earlier in the year. That downturn forced many private practitioners to contemplate selling their practices.

In a survey released this summer by McKinsey & Company, 53% of independent physicians reported that they were worried about their practices surviving. Although many physicians have now reopened their offices, patient volume is reduced, and physicians are earning far less than before.

“In many cases, physicians who had been considering retirement in the next few years have moved their planning up and want to sell as soon as possible,” said John D. Fanburg, an attorney at Brach Eichler, a law firm in Roseland, N.J., who specializes in medical practice sales and mergers.

“For physicians over age 65, it’s not just worries about finances; it’s also worries about the health risks of staying open,” Mr. Fanburg added.

Mid-career physicians are also selling their practices. Many of them become employees of the hospital, large practice, or private-equity firm that bought the practice – receiving a level of compensation set by the sales agreement.
 

Will your practice be hard to sell?

With so many physicians ready to sell, are there enough potential buyers to acquire them all? Probably not, said Mr. Dietrich.

“Many hospitals may not need new practices right now,” he said. “In the depths of the pandemic, they furloughed many of their existing doctors and may not have brought all of them back yet.”

In fact, because of the pandemic, some buyers have delayed sales that were already in progress, said Monica H. Kaden, director of business valuations at Sobel Valuations, based in Livingston, N.J.

“Buyers are not only worried about their own cash flow but also about the possibility of lower revenues of the selling practices due to COVID-19,” she said, citing a very large multispecialty group that has put its purchase of a another large multispecialty group on hold.
 

Practice values have (temporarily) fallen

Many potential buyers are still looking, though. One thing that drives them is the possibility of discounted sales because of COVID-19. “The sense I get is that a lot of hospitals see this as an opportunity to pick up practices on the cheap,” Mr. Dietrich said.

COVID-19 has been reducing practice values somewhat, said Reed Tinsley, a CPA in Houston who performs medical practice valuations and runs a practice brokerage firm. “Practice revenues and net income are lower under COVID-19, so prices are lower.”

Ms. Kadan advised physicians to hold off selling if they can afford to wait. “It’s always best to sell when the practice volume looks the best, because then the practice is worth more. But there are doctors who can’t wait because revenues are really falling and they are running out of money. They may have no choice but to sell.”

Even in the best of times, not all practices can be sold, said Sean Tinsley, a broker and licensed financial adviser at Tinsley Medical Practice Brokers in Austin, Tex., which he runs with his father, Reed Tinsley.

“We turn down about as many deals to sell practices as we accept,” he said. “Brokers have to be very selective because we don’t get paid until the practice gets sold. Generally, we won’t take practices in rural areas or practices that still only have a fraction of their pre–COVID-19 volume.”
 

How long will it take to sell your practice?

Some practices find a buyer within weeks, but in other cases, it can take as long as a year, he said. Once the buyer is located, preparing the paperwork for the sale can take 45-60 days.

Doctors can sell their practices on their own, but a broker can help them find potential buyers and select the right price. Business brokers generally receive a greater percentage of the sales price than residential brokers. They have greater command of business and finance, and the sale is more complex than a residential sale.

The broker may also help with selling the building where the practice is located, which is usually a separate sale, said Bruce E. Wood, an attorney at CCB Law in Syracuse, N.Y., who deals with practice sales. “A hospital buying your practice may not want to buy the building, so it has to be sold separately. You can always sell the space to a different buyer.”
 

What’s the right price for your practice?

For small practices, brokers often set a price by establishing a multiple, such as two times net earnings, Sean Tinsley said. In many cases, practices haven’t retained net earnings, so the broker uses gross annual revenue and sets the price at 50%-55% of that figure.

An alternative that is widely used in the business world and for many large practices is to base the price on earnings before interest, taxes, depreciation, and amortization (EBITDA). To determine a price, the EBITDA is then multiplied by a particular multiple, which depends on the perceived value of the practice.

Higher multiples go to practices that have a qualified management team, have documented financial policies and procedures, or have had significant past growth. Generally, the multiple of EBITDA at smaller practices is 1 or 2; larger practices have a multiple of 5-7 times EBITDA, Sean Tinsley said.

COVID-19 has had the effect of reducing the multiple somewhat. “As market forces shift from a seller’s market to a buyer’s market, multiples will likely remain below pre–COVID-19 levels for the remainder of 2020 and the first half of 2021,” one report stated.

Certified valuators like Reed Tinsley have more complex ways to establish the value of a practice, but as a broker, Sean Tinsley tends to use the multiples approach. He asserted that the prices derived from this method are on the mark. “Almost all the time we sell at the asking price.”
 

Using valuations to set the price

A more complex and expensive way to set a price for a practice is to order a valuation of the practice. The valuator issues a report that runs dozens of pages and costs thousands of dollars.

Mr. Fanburg said that very few physicians selling practices order valuation reports, owing to the cost and complexity. As a result, “they don’t have a clear idea what their practices are worth.”

A comprehensive report is called a conclusion of value. The amount it finds – expressed as a range – is called “fair market value.” The report can be used in the courts for legal disputes as well as for deriving a sales price.

Practices that don’t want to pay for a conclusion of value can ask a valuator to assemble a less extensive report, called an opinion of calculated value. Also known as a calculation engagement or engagement letter, it still costs several thousand dollars.

This report has limited validity and can’t be used in the courts, according to Jarrod Barraza, a certified valuator in the Nashville, Tenn., office of Horne, a health care business valuator. “When I issue an engagement letter, I am not talking as an appraiser but as a valuation consultant, and I don’t call the result fair market value; it’s only estimating,” he said.

For all of the precision of formal reports, however, valuations of a practice can vary widely, according to Reed Tinsley. “Two valuations using the same methodology can differ by $300,000.”

Also, the valuation can be well above a reasonable asking price, said Sean Tinsley. “The market dictates the price. A traditional valuation almost invariably quotes a higher return than the market is willing to pay.”
 

Buyers’ valuations

Physicians who decide not to get a valuation still have to deal with valuations ordered by buyers. Hospitals and large practices often order valuations of the practices they want to buy, and private-equity firms use methods much like a valuation for the practices they are interested in.

Buyers rarely share the valuation report with the seller, so the seller has to accept the buyer’s price without being able to review the thought process behind it, Mr. Fanburg said. “Relying on the buyer to tell you what you’re worth means you may sell your practice well below its true value.”

When the buyer orders a valuation, the valuator interviews managers of the practice and asks for a great deal of information, says G. Don Barbo, managing director at VMG Health, a health care valuation firm based in Dallas.

Mr. Barbo said these documents include financial statements for the practice, usually going back 3-5 years; productivity reports for doctors and other providers; accounts receivables; reports of fixed assets; a roster of employees; employment agreements and management services agreements; reports on payer mix; facility leases and equipment lease agreements; budgets and projections; and tax returns.

Mr. Dietrich said valuators hone in on the practice’s current procedural terminology codes. “If the practice is coding too high, this would artificially increase the profit and purported value of the practice. For example, coding at 99214 rather than 99213 for an established patient means that the practice is being paid 45% more for each visit.” The valuator then reduces the value of the practice on the basis of the extent of the improper up-coding.

Mr. Barbo said some sellers don’t want all the scrutiny of the buyer’s valuation and just sell the practice’s tangible assets – furnishings, fixtures, and equipment – which do not require a great deal of documentation but yield a much lower price.
 

A primer on valuations

As a valuator, “my job is to project into the future,” Mr. Barraza said. “I am trying to see how the practice will fare going forward.”

Mr. Dietrich agreed, with one caveat: “As Yogi Berra said: ‘It’s difficult to make predictions, especially about the future.’ ”

The formal valuation assesses the practice in three ways: measuring income, assets, and what other practices sell for, called the market approach.

With the income approach, the most used measurement for practices, one tries to determine future income, which is what buyers are most interested in, Mr. Dietrich said. The income equals revenue (total collections) minus operating expenses and overhead.

“You are then left with all the money the physician is paid,” he said. “The issue is, how much is attributed to the physician’s own labor and how much to his or her ownership of the practice? This second category helps determine the value of the practice.”

The market approach is often used as a way to double-check the accuracy of the income approach. The appraiser looks for the prices of similar practices that have already been sold and then adjusts the price on the basis of differences with the practice up for sale.

The asset approach may be used when the practice has no positive cash flow. It establishes a price for tangible assets, which are often much lower in value than the values that the other approaches come up with. The asset approach can be a lower-priced alternative for practices that can’t be measured under the income or market approach.

“Equipment appraisers can do an inventory of your equipment,” Mr. Wood said. “Generally, equipment that is more than 3 years old, such as computers, is not that valuable, but an ultrasound machine probably has some resale value.”
 

Will the buyer pay for goodwill?

Many practice owners hope they can get money for the “goodwill” of their practice when they sell. Goodwill basically represents the reputation of the practice, which is difficult to pinpoint, and Mr. Wood said buyers often don’t want to pay for it.

“The goodwill is a wild card,” Mr. Wood said. “It can range from zero to crazy numbers. There is a Goodwill Registry – a list of the goodwill in other practice sales – that you can consult.”

One simple way to calculate the goodwill, he said, is to take the value of the practice based on examining income and remove the value of tangible assets. What is left is considered the goodwill.

Another form of intangible asset that is sometimes lumped together with goodwill is the value of the practice’s trained staff. “Some buyers agree to pay for the staff in place, because they plan to use that staff,” Ms. Kadan said. In one large deal she was involved with, the buyer agreed to pay something for the selling practice’s staff of 180 people.

Another item that buyers also do not typically pay for is the practice’s accounts receivable. They may also not pay for any liabilities the practice holds, such as the facility lease, equipment lease, and maintenance contracts, Mr. Barbo said. “The buyer then often stipulates that all liabilities are left to the practice, or stipulates any specific liabilities that it may assume.”
 

Selling to other doctors

Doctors can sell practices or shares in practices to other doctors. A retiring physician, for example, can sell his or her share to the other partners. A valuator may be brought in to establish the value of the doctor’s equity interest in the practice.

“Generally, practice buyouts aren’t lucrative for selling physician,” Mr. Wood said. “There are exceptions, of course, such as specialty practices in some cases.”

A practice can also be sold to a new doctor or to a previously employed physician who wants to be an owner. These physicians usually need to get a bank loan to buy the practice.

The bank assesses the finances of the selling practice to determine whether the buying physician will earn enough money to pay back the loan. “Banks don’t want lend more than the gross annual revenue of the practice, and some banks will only lend at 65% of gross annual revenue,” Sean Tinsley said.

COVID-19 has seriously affected banks’ lending decisions. Banks stopped lending to practice buyers at the beginning of the pandemic, and when they started lending again, they were more cautious, Sean Tinsley said. “Generally, banks want to see the practice at 85%-90% of pre–COVID-19 numbers before they make a loan.”

He added that, if a buyer can’t get a bank loan, the selling doctor may decide to finance the sale. The buyer agrees to a payment schedule to pay off the full price over several years.
 

Selling to or merging with other practices

The usual buyer is another practice, Reed Tinsley said. “You can sell to a group, but prices are low because, with COVID-19, buyers don’t want to incur a lot of money up front. Or you can merge with the practice, which means the selling doctor usually doesn’t get any money, but he does get a share in the larger practice. In that case, the partnership is the object of value, and it can be cashed out when the physician leaves the practice.”

Mergers can get very complicated. Mr. Fanburg said he has been working with seven groups that are merging into one. “The merger was scheduled to go live last January, but it was slowed down over negotiations about new managed care contracts and putting together a management structure, plus the groups were a little wary of each other. Now the deal is scheduled to go live next January.”

One advantage to selling to a larger entity, such as a big group practice or a hospital, is that the selling physician benefits from the higher reimbursement rates that large providers usually command. “If the buyer has more favorable reimbursement rates with insurers, it could pay the selling doctor much more than he is making now,” Mr. Barraza said.
 

Hospitals as buyers

Because of COVID-19, currently many hospitals don’t have money to buy more practices. However, this is most likely a temporary situation.

Hospitals typically offer less money than other buyers, according to Sean Tinsley. “We have never sold to a hospital, because hospitals generally don’t pay for goodwill. They pay for the practice assets and offer a dollar amount for each chart.”

Hospitals have to be careful not to pay physicians more than the usual amount for their practices, because the extra amount could be seen as a kickback for referrals, which would violate the federal Stark law and Anti-Kickback Statute. Not-for-profit hospitals also have to comply with regulations at the Internal Revenue Service.

Hospitals usually require that the selling physician continue to work in the practice after it is sold. The selling physician’s presence helps ensure that the practice’s output will not decline after sale. Although the sales price may be low, the hospital may make up for it by paying a higher compensation, Sean Tinsley said.
 

Selling to private-equity firms

Private-equity purchases are financed by investors who essentially want to “flip” practices – that is, they want to make them more profitable and then sell them to someone else. The private-equity firm starts by buying a “platform” practice, which forms the core of the venture. It then buys smaller practices that will be managed by the platform practice.

The number of private-equity deals increased continually through 2019, then plummeted in March because of COVID-19, but by the summer, activity began to rise again.

Physicians are very intrigued about selling to private-equity firms because they are known to pay the most for practices. But private-equity buyers focus on a fairly narrow group of specialties.

Generally, Sean Tinsley said, private-equity firms only look for pain, dermatology, and ophthalmology practices, but they have been starting to branch out to specialties such as gastroenterology. In 2018, there were only two private-equity deals for gastroenterology practices, but in 2019, there were 16, according to one assessment.

Private-equity firms buy very few of the practices they initially review, according to Mr. Fanburg. “Private equity negotiates with dozens or even hundreds of physician practices at a time, with only 1%-5% of those practices actually being acquired.”

The private-equity firm’s upfront payment to selling physicians is quite high, but then the physicians become employees of the new group and earn much less in compensation than they earned on this own.

“In order for the venture to get any value out of the acquisition, the doctors have to make less going forward than they did historically,” Mr. Dietrich said. That freed-up money boosts the value of the venture.

When the platform practice is sold – usually after 5 years or so – “chances are the management team will be replaced,” Mr. Fanburg said. “There could be new policies and objectives, which could mean a bumpy ride for physicians.”
 

Do you really want to sell?

“When a group of physicians comes to me asking for help selling their practice, my first question is, Why are you doing this?” Mr. Fanburg said. “You need a better reason for selling than just the money.

“Once you make the leap, there is a certain amount of autonomy you lose,” he continued. “The sale gives you an economic boost, but it may not be enough for the long haul. If you stay on with the buyer, your compensation is often lower. That makes sense if you’re retiring, but not if you’re a younger physician with many years of practice in the years ahead.

“When physicians say they see no other way out except to sell,” Mr. Fanburg said, “I tell them that their buyer will see a path to future growth for your practice. If you think reimbursements are getting worse, why are the buyers pressing ahead?”

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