Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.

Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.

In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
 

Cohort study

The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.

Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.

The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.

From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.

For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).

The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).

As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).

In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.

Of the patients still alive at the end of the follow-up period, 38% had active HCC.
 

Long-term follow-up required

“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.

“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.

Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.

“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.

Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.

The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.

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

Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.

Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.

In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
 

Cohort study

The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.

Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.

The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.

From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.

For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).

The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).

As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).

In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.

Of the patients still alive at the end of the follow-up period, 38% had active HCC.
 

Long-term follow-up required

“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.

“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.

Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.

“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.

Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.

The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.

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

Although the risk for liver cancer diminishes for patients with hepatitis C virus (HCV) infections for whom the virus is eliminated with direct-acting antiviral (DAA) drugs, these patients are not out of the woods, and those who do not have a sustained viral response (SVR) are at substantially higher risk of developing hepatocellular carcinoma (HCC), results of a large study show.

Among the patients with liver cirrhosis from HCV infections treated at 30 centers in Italy, a large percentage had an SVR after treatment with DAA drugs. Only a small percentage of this group subsequently developed HCC.

In contrast, not having an SVR was associated with a more than sevenfold higher risk for liver cancer, said Loreta A. Kondili, MD, PhD, from the Center for Global Health at the Istituto Superiore di Sanità, Rome, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Failure to achieve SVR after DAA treatment is strongly associated with the probability of HCC development. Older age, [HCV] genotype 3, and low platelet counts and albumin levels are independent factors of HCC development despite viral eradication,” she said.
 

Cohort study

The study findings come from the PITER Cohort Study, a prospective, multicenter observational study of a representative sample of patients with HCV.

Dr. Kondili and colleagues assessed the medium- and long-term effects of DAA therapy on HCC rates among patients with HCV-induced liver cirrhosis. Patients who had undergone a liver transplant or who had been previously diagnosed with HCC were excluded.

The investigators identified a total of 2,214 DAA-treated patients, of whom 149 (6.7%) developed de novo HCC after a median follow-up of 30 months.

From the total group, 2,064 (93%) patients had an SVR, 119 of whom (5.8%) developed HCC. Of these patients who developed HCC, 80% were diagnosed with stage B or C disease in accordance with the Barcelona Clinic Liver Cancer staging system.

For the remaining 150 patients who did not have an SVR, 30 (20%) developed de novo HCC, a difference that translated into an adjusted hazard ratio (aHR) for HCC of 7.38 (P < .01).

The time from the end of DAA therapy to a diagnosis of HCC was shorter for patients who did not have an SVR. For these patients, the 2-year HCC-free survival rate was 81%, compared with 98% for patients who had an SVR (P < .001).

As reported by Dr. Kondili, among patients who achieved an SVR, the variables significantly associated with HCC risk included older age (aHR, 1.06), platelet counts greater than the reference limit of 150,000 μL (aHR, 2.43), albumin levels >3.5 g/dL (aHR, 2.36), and diabetes (aHR, 1.53; all these variables were significant by confidence intervals).

In all, 26% of these patients died during the follow-up period, and 7.6% underwent liver transplant.

Of the patients still alive at the end of the follow-up period, 38% had active HCC.
 

Long-term follow-up required

“It’s useful to think of hepatitis C as a viral infection on one hand [and] a liver disease on the other,” commented Raymond T. Chung, MD, director of the Hepatology and Liver Center and vice chief of gastroenterology at Massachusetts General Hospital, Boston.

“In terms of thinking of elimination, we can eradicate the virus in most patients with virtually 100% success with antivirals. This has given us a false sense of comfort that it’s a ‘one and done’ process, and patients can more or less enjoy the rest of their lives free of hepatitis C,” he said.

Dr. Chung, who was not involved in the study, emphasized that despite the elimination of the virus, patients may still have significant liver fibrosis or cirrhosis. It is imperative that these patients be monitored for signs of cancer, he said.

“This is what’s important about staging patients and understanding how severe their liver disease is, because if there is advanced fibrosis, bridging fibrosis, or cirrhosis, these are patients who are going to require long-term oncology care. Their infectious disease is eliminated, but the liver disease remains,” he said.

Dr. Chung also noted that rates of liver cancer, decompensation, and liver failure are higher among patients with untreated HCV than among patients whose HCV has been eradicated or suppressed with drug treatment. In addition, patients with untreated HCV are at greater risk of requiring transplant than are patients with HCV that was treated, and there remains a residual cancer risk for patients who become HCV seronegative.

The study was funded by the Italian Ministry of Health. Dr. Kondili has financial relationships with Gilead Science and AbbVie. Dr. Chung reported no relevant financial relationships.

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

A high rate of bullying towards U.K. cardiology trainees by their superiors has been revealed in a new survey. More than 10% of doctors training to be cardiologists in the United Kingdom say they have been bullied in the last 4 weeks, and one-third report having witnessed bullying on a cardiology rotation, the survey reports.

In addition, 33% of cardiology trainees said they had been on the receiving end of inappropriate behavior, including having their opinions and views ignored, being made to feel worthless/useless, and being shouted at or targeted with spontaneous anger.

Senior doctors (consultants) in cardiology were cited as the main perpetrators of such bullying and inappropriate behavior.

Women trainee cardiologists and those who attended medical school outside the United Kingdom were more likely to report having been bullied, suggesting a sexist and racist element.

“In this large and repeated survey of British cardiology trainees, we have shown a persistent and important problem with bullying,” the authors conclude.

Results of the survey from the British Junior Cardiologists’ Association, were published online in a paper in Heart on Dec. 6, 2021.

Examples of such bullying behavior by consultant cardiologists toward their trainees reported in the survey included being belittled in front of others, having their filing cabinet drawer thrown across the room, use of foul language toward trainees, and using previous mistakes as an excuse to humiliate and ridicule them, lead author of the survey, Christian Fielder Camm, MD, Keble College, Oxford (England) University, told this news organization.

Trainees also reported being made to feel inadequate when struggling to achieve unrealistic tasks and being pressured into not taking holidays and study leave.

Many respondents said they did not report such behavior for fear of repercussions and in some cases because the perpetrators were known for their bullying behavior, and previous attempts to intervene had not resulted in any change.

Dr. Camm, who is a cardiology trainee himself, says he has not personally been the victim of bullying, but as secretary of the BJCA he regularly receives reports about it happening.

“We wanted to look at this issue in our survey as we had been hearing anecdotal reports of bullying from cardiology trainees for a number of years,” Dr. Camm said. “We wanted to put it out there that this is not just an isolated issue and shine a light on the problem.”

Noting that the U.K. General Medical Council’s annual survey has found that bullying is seen across all disciplines in medicine, Dr. Camm said that cardiology has the highest reported rate of bullying among the medical specialties.

“This is not a new story – it has been played out throughout history, but things are not magically improving. Over the 4 years of our survey, rates of reported bullying have stayed the same,” he noted. “Our survey is asking more questions about bullying to find more detail on what is happening.”

The current data come from the BJCA annual survey from 2017 to 2020. As part of the survey, trainee cardiologists were asked about direct and indirect experiences of bullying and inappropriate language/behavior in cardiology departments in the preceding 4 weeks.

In all, 2,057 responses were received, 73% were from men, and the average age of respondents was 33 years. Over half (59%) were working in a specialist center for cardiology (tertiary referral center), and 94% had a national training number, which guarantees a continued place on a training program, subject to performance.

“This project has upset me to realize what my colleagues are experiencing. This is the working environment we are creating, and it is not good enough,” Dr. Camm said.

At present, the bullying behavior is not often reported. “Usually, the only person to report it to is the senior person in the department, who is frequently the cause of the problem, so most people just put up with it until they move on to their next training rotation. The working environment should not be so difficult,” he said.

The authors noted that bullying has been shown to significantly affect trainees, with those subject to bullying being 70% more likely to report serious or potentially serious medical errors, and more likely to take time off work and cease direct patient care.

They stressed that addressing bullying of trainees needs to be a priority both to ensure patient safety and to reduce trainee attrition in a time of unprecedented workforce pressures.

Dr. Camm believes a national plan needs to be put in place to deal with this issue and said the BJCA is keen to work with the British Cardiovascular Society to develop a zero-tolerance policy, with a clear strategy to address allegations of bullying.

“The world is changing. Hopefully this publication will be the start of some change,” he added.
 

Bullying culture is ‘endemic’

In an accompanying editorial, consultant cardiologist Resham Baruah, MBBS, PhD, of Chelsea and Westminster Healthcare NHS Trust, London, and independent professional coach Emma Sedgwick said the findings offer a “sobering insight into current practice” and indicate that “a bullying culture is endemic in many U.K. cardiology departments.”

“These trainee cardiologists are actually quite senior doctors with many years of experience. They work extremely hard. These surveys show that we are not valuing them enough,” Dr. Baruah said in an interview.

“Cardiology is a really competitive specialty. There is a lot of pressure. All the way through training the message is competitive,” she said. “Being collegiate and working as a team is not rewarded. We have to rethink this as we train the next generation.”

“We believe that publishing these data acknowledges bullying is not going unnoticed, although this alone is not enough,” the editorialists said.

Noting that labels matter, they propose a rejection of the term “juniors” and a return to the old system of calling colleagues senior house officers, registrars, and senior registrars.

They also proposed sanctions for institutions that ignore bullying, but stress that better working conditions for all staff are needed.

“Bullies are usually feeling defensive, overwhelmed, and stressed and take these feelings out on others,” Dr. Baruah commented. “I think what we are seeing in this paper is not just restricted to cardiology but happens all though the NHS and is related to workload, lack of autonomy, and burnout. Work culture is crucial to well-being and job satisfaction. Nobody wants to work in a toxic environment.”

She emphasized that bullying behaviors must not be accepted. “They can have catastrophic consequences for the trainees and for patient safety. While working in high-pressure specialties and emergency situations may foster such behavior, it is vitally important to arm trainees with the recognition of bullying and how to deal with it. They must feel empowered to speak up in an appropriate way.”

The editorialists noted that the Royal College of Obstetricians and Gynaecologists responded to high levels of bullying by creating behavior toolkits, workshops, and behavior champions. “This survey should act as a call to arms for cardiology to introduce similar initiatives,” they stated.

“While times are changing, the corporate environment has moved forward in encouraging positive workplace behavior faster than is happening in medicine,” Dr. Baruah said. “But there is an appetite for change. We have to have an environment where people can speak up.”

The study received no specific funding. The authors reported no competing interests.

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

A high rate of bullying towards U.K. cardiology trainees by their superiors has been revealed in a new survey. More than 10% of doctors training to be cardiologists in the United Kingdom say they have been bullied in the last 4 weeks, and one-third report having witnessed bullying on a cardiology rotation, the survey reports.

In addition, 33% of cardiology trainees said they had been on the receiving end of inappropriate behavior, including having their opinions and views ignored, being made to feel worthless/useless, and being shouted at or targeted with spontaneous anger.

Senior doctors (consultants) in cardiology were cited as the main perpetrators of such bullying and inappropriate behavior.

Women trainee cardiologists and those who attended medical school outside the United Kingdom were more likely to report having been bullied, suggesting a sexist and racist element.

“In this large and repeated survey of British cardiology trainees, we have shown a persistent and important problem with bullying,” the authors conclude.

Results of the survey from the British Junior Cardiologists’ Association, were published online in a paper in Heart on Dec. 6, 2021.

Examples of such bullying behavior by consultant cardiologists toward their trainees reported in the survey included being belittled in front of others, having their filing cabinet drawer thrown across the room, use of foul language toward trainees, and using previous mistakes as an excuse to humiliate and ridicule them, lead author of the survey, Christian Fielder Camm, MD, Keble College, Oxford (England) University, told this news organization.

Trainees also reported being made to feel inadequate when struggling to achieve unrealistic tasks and being pressured into not taking holidays and study leave.

Many respondents said they did not report such behavior for fear of repercussions and in some cases because the perpetrators were known for their bullying behavior, and previous attempts to intervene had not resulted in any change.

Dr. Camm, who is a cardiology trainee himself, says he has not personally been the victim of bullying, but as secretary of the BJCA he regularly receives reports about it happening.

“We wanted to look at this issue in our survey as we had been hearing anecdotal reports of bullying from cardiology trainees for a number of years,” Dr. Camm said. “We wanted to put it out there that this is not just an isolated issue and shine a light on the problem.”

Noting that the U.K. General Medical Council’s annual survey has found that bullying is seen across all disciplines in medicine, Dr. Camm said that cardiology has the highest reported rate of bullying among the medical specialties.

“This is not a new story – it has been played out throughout history, but things are not magically improving. Over the 4 years of our survey, rates of reported bullying have stayed the same,” he noted. “Our survey is asking more questions about bullying to find more detail on what is happening.”

The current data come from the BJCA annual survey from 2017 to 2020. As part of the survey, trainee cardiologists were asked about direct and indirect experiences of bullying and inappropriate language/behavior in cardiology departments in the preceding 4 weeks.

In all, 2,057 responses were received, 73% were from men, and the average age of respondents was 33 years. Over half (59%) were working in a specialist center for cardiology (tertiary referral center), and 94% had a national training number, which guarantees a continued place on a training program, subject to performance.

“This project has upset me to realize what my colleagues are experiencing. This is the working environment we are creating, and it is not good enough,” Dr. Camm said.

At present, the bullying behavior is not often reported. “Usually, the only person to report it to is the senior person in the department, who is frequently the cause of the problem, so most people just put up with it until they move on to their next training rotation. The working environment should not be so difficult,” he said.

The authors noted that bullying has been shown to significantly affect trainees, with those subject to bullying being 70% more likely to report serious or potentially serious medical errors, and more likely to take time off work and cease direct patient care.

They stressed that addressing bullying of trainees needs to be a priority both to ensure patient safety and to reduce trainee attrition in a time of unprecedented workforce pressures.

Dr. Camm believes a national plan needs to be put in place to deal with this issue and said the BJCA is keen to work with the British Cardiovascular Society to develop a zero-tolerance policy, with a clear strategy to address allegations of bullying.

“The world is changing. Hopefully this publication will be the start of some change,” he added.
 

Bullying culture is ‘endemic’

In an accompanying editorial, consultant cardiologist Resham Baruah, MBBS, PhD, of Chelsea and Westminster Healthcare NHS Trust, London, and independent professional coach Emma Sedgwick said the findings offer a “sobering insight into current practice” and indicate that “a bullying culture is endemic in many U.K. cardiology departments.”

“These trainee cardiologists are actually quite senior doctors with many years of experience. They work extremely hard. These surveys show that we are not valuing them enough,” Dr. Baruah said in an interview.

“Cardiology is a really competitive specialty. There is a lot of pressure. All the way through training the message is competitive,” she said. “Being collegiate and working as a team is not rewarded. We have to rethink this as we train the next generation.”

“We believe that publishing these data acknowledges bullying is not going unnoticed, although this alone is not enough,” the editorialists said.

Noting that labels matter, they propose a rejection of the term “juniors” and a return to the old system of calling colleagues senior house officers, registrars, and senior registrars.

They also proposed sanctions for institutions that ignore bullying, but stress that better working conditions for all staff are needed.

“Bullies are usually feeling defensive, overwhelmed, and stressed and take these feelings out on others,” Dr. Baruah commented. “I think what we are seeing in this paper is not just restricted to cardiology but happens all though the NHS and is related to workload, lack of autonomy, and burnout. Work culture is crucial to well-being and job satisfaction. Nobody wants to work in a toxic environment.”

She emphasized that bullying behaviors must not be accepted. “They can have catastrophic consequences for the trainees and for patient safety. While working in high-pressure specialties and emergency situations may foster such behavior, it is vitally important to arm trainees with the recognition of bullying and how to deal with it. They must feel empowered to speak up in an appropriate way.”

The editorialists noted that the Royal College of Obstetricians and Gynaecologists responded to high levels of bullying by creating behavior toolkits, workshops, and behavior champions. “This survey should act as a call to arms for cardiology to introduce similar initiatives,” they stated.

“While times are changing, the corporate environment has moved forward in encouraging positive workplace behavior faster than is happening in medicine,” Dr. Baruah said. “But there is an appetite for change. We have to have an environment where people can speak up.”

The study received no specific funding. The authors reported no competing interests.

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

A high rate of bullying towards U.K. cardiology trainees by their superiors has been revealed in a new survey. More than 10% of doctors training to be cardiologists in the United Kingdom say they have been bullied in the last 4 weeks, and one-third report having witnessed bullying on a cardiology rotation, the survey reports.

In addition, 33% of cardiology trainees said they had been on the receiving end of inappropriate behavior, including having their opinions and views ignored, being made to feel worthless/useless, and being shouted at or targeted with spontaneous anger.

Senior doctors (consultants) in cardiology were cited as the main perpetrators of such bullying and inappropriate behavior.

Women trainee cardiologists and those who attended medical school outside the United Kingdom were more likely to report having been bullied, suggesting a sexist and racist element.

“In this large and repeated survey of British cardiology trainees, we have shown a persistent and important problem with bullying,” the authors conclude.

Results of the survey from the British Junior Cardiologists’ Association, were published online in a paper in Heart on Dec. 6, 2021.

Examples of such bullying behavior by consultant cardiologists toward their trainees reported in the survey included being belittled in front of others, having their filing cabinet drawer thrown across the room, use of foul language toward trainees, and using previous mistakes as an excuse to humiliate and ridicule them, lead author of the survey, Christian Fielder Camm, MD, Keble College, Oxford (England) University, told this news organization.

Trainees also reported being made to feel inadequate when struggling to achieve unrealistic tasks and being pressured into not taking holidays and study leave.

Many respondents said they did not report such behavior for fear of repercussions and in some cases because the perpetrators were known for their bullying behavior, and previous attempts to intervene had not resulted in any change.

Dr. Camm, who is a cardiology trainee himself, says he has not personally been the victim of bullying, but as secretary of the BJCA he regularly receives reports about it happening.

“We wanted to look at this issue in our survey as we had been hearing anecdotal reports of bullying from cardiology trainees for a number of years,” Dr. Camm said. “We wanted to put it out there that this is not just an isolated issue and shine a light on the problem.”

Noting that the U.K. General Medical Council’s annual survey has found that bullying is seen across all disciplines in medicine, Dr. Camm said that cardiology has the highest reported rate of bullying among the medical specialties.

“This is not a new story – it has been played out throughout history, but things are not magically improving. Over the 4 years of our survey, rates of reported bullying have stayed the same,” he noted. “Our survey is asking more questions about bullying to find more detail on what is happening.”

The current data come from the BJCA annual survey from 2017 to 2020. As part of the survey, trainee cardiologists were asked about direct and indirect experiences of bullying and inappropriate language/behavior in cardiology departments in the preceding 4 weeks.

In all, 2,057 responses were received, 73% were from men, and the average age of respondents was 33 years. Over half (59%) were working in a specialist center for cardiology (tertiary referral center), and 94% had a national training number, which guarantees a continued place on a training program, subject to performance.

“This project has upset me to realize what my colleagues are experiencing. This is the working environment we are creating, and it is not good enough,” Dr. Camm said.

At present, the bullying behavior is not often reported. “Usually, the only person to report it to is the senior person in the department, who is frequently the cause of the problem, so most people just put up with it until they move on to their next training rotation. The working environment should not be so difficult,” he said.

The authors noted that bullying has been shown to significantly affect trainees, with those subject to bullying being 70% more likely to report serious or potentially serious medical errors, and more likely to take time off work and cease direct patient care.

They stressed that addressing bullying of trainees needs to be a priority both to ensure patient safety and to reduce trainee attrition in a time of unprecedented workforce pressures.

Dr. Camm believes a national plan needs to be put in place to deal with this issue and said the BJCA is keen to work with the British Cardiovascular Society to develop a zero-tolerance policy, with a clear strategy to address allegations of bullying.

“The world is changing. Hopefully this publication will be the start of some change,” he added.
 

Bullying culture is ‘endemic’

In an accompanying editorial, consultant cardiologist Resham Baruah, MBBS, PhD, of Chelsea and Westminster Healthcare NHS Trust, London, and independent professional coach Emma Sedgwick said the findings offer a “sobering insight into current practice” and indicate that “a bullying culture is endemic in many U.K. cardiology departments.”

“These trainee cardiologists are actually quite senior doctors with many years of experience. They work extremely hard. These surveys show that we are not valuing them enough,” Dr. Baruah said in an interview.

“Cardiology is a really competitive specialty. There is a lot of pressure. All the way through training the message is competitive,” she said. “Being collegiate and working as a team is not rewarded. We have to rethink this as we train the next generation.”

“We believe that publishing these data acknowledges bullying is not going unnoticed, although this alone is not enough,” the editorialists said.

Noting that labels matter, they propose a rejection of the term “juniors” and a return to the old system of calling colleagues senior house officers, registrars, and senior registrars.

They also proposed sanctions for institutions that ignore bullying, but stress that better working conditions for all staff are needed.

“Bullies are usually feeling defensive, overwhelmed, and stressed and take these feelings out on others,” Dr. Baruah commented. “I think what we are seeing in this paper is not just restricted to cardiology but happens all though the NHS and is related to workload, lack of autonomy, and burnout. Work culture is crucial to well-being and job satisfaction. Nobody wants to work in a toxic environment.”

She emphasized that bullying behaviors must not be accepted. “They can have catastrophic consequences for the trainees and for patient safety. While working in high-pressure specialties and emergency situations may foster such behavior, it is vitally important to arm trainees with the recognition of bullying and how to deal with it. They must feel empowered to speak up in an appropriate way.”

The editorialists noted that the Royal College of Obstetricians and Gynaecologists responded to high levels of bullying by creating behavior toolkits, workshops, and behavior champions. “This survey should act as a call to arms for cardiology to introduce similar initiatives,” they stated.

“While times are changing, the corporate environment has moved forward in encouraging positive workplace behavior faster than is happening in medicine,” Dr. Baruah said. “But there is an appetite for change. We have to have an environment where people can speak up.”

The study received no specific funding. The authors reported no competing interests.

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

This month marks the end of my first full calendar year as SHM CEO. Over the years, I have made it a habit to take time to reflect during the month of December, assessing the previous year by reviewing what went well and what could have gone better, and how I can grow and change to meet the needs of future challenges. This reflection sets the stage for my personal and professional “New Year” goals.

This year, 2021, is certainly a year deserving of reflection, and I believe 2022 (and beyond) will need ambitious goals made by dedicated leaders, hospitalists included. Here are my thoughts on what went well in 2021 and what I wish went better – from our greater society to our specialty, to SHM.
 

Society (as in the larger society)

What went well: Vaccines

There is a lot to be impressed with in 2021, and for me, at the top of that list are the COVID-19 vaccines. I realize the research for mRNA vaccines started more than 20 years ago, and the most successful mRNA vaccine companies have been around for more than a decade, but to roll out a COVID-19 vaccine in less than a year is still just incredible. To take a disease with a 2% mortality rate for someone like myself and effectively reduce that to near zero is something historians will be writing about for years to come.

What I wish went better: Open dialogue

I can’t remember when we stopped listening to each other, and by that, I mean listening to those who do not think exactly like ourselves. As a kid, I was taught to be careful about discussing topics at social events that could go sideways. That usually involved politics, money, or strong beliefs, but wow – now, that list is much longer. Talking about the weather used to be safe, but not anymore. If I were to show pictures of the recent flooding in Annapolis? There would almost certainly be a debate about climate change. At least we can agree on Ted Lasso as a safe topic.

Our specialty

What went well: Hospitalists are vital

There are many, many professions that deserve “hero” status for their part in taming this pandemic: nurses, doctors, emergency medical services, physical therapists, physician assistants, nurse practitioners, administrators, and more. But in the doctor category, hospitalists are at the top. Along with our emergency department and intensivist colleagues, hospitalists are one of the pillars of the inpatient response to COVID. More than 3.2 million COVID-19 hospitalizations have occurred, according to the Centers for Disease Control and Prevention, with numerous state dashboards showing three-quarters of those are cared for on general medical wards, the domain of hospitalists (for example, see my own state of Maryland’s COVID-19 dashboard: https://coronavirus.maryland.gov).

We’ve always had “two patients” – the patient in the bed and the health care system. Many hospitalists have helped their institutions by building COVID care teams, COVID wards, or in the case of Dr. Mindy Kantsiper, building an entire COVID field hospital in a convention center. Without hospitalists, both patients and the system that serves them would have fared much worse in this pandemic. Hospitalists are vital to patients and the health care system. The end. Period. End of story.
 

What I wish went better: Getting credit

As a profession, we need to be more deliberate about getting credit for the fantastic work we have done to care for COVID-19 patients, as well as inpatients in general. SHM can and must focus more on how to highlight the great work hospitalists have done and will continue to do. A greater understanding by the health care industry – as well as the general public – regarding the important role we play for patient care will help add autonomy in our profession, which in turn adds to resilience during these challenging times.

SHM

What went well: Membership grew

This is the one thing that we at SHM – and I personally – are most proud of. SHM is a membership society; it is the single most important metric for me personally. If physicians aren’t joining, then we are not meeting our core mission to provide value to hospitalists. My sense is the services SHM provides to hospitalists continue to be of value – even during these strenuous times of the pandemic when we had to be physically distant.

Whether it’s our Government Relations Department advocating for hospitalists in Washington, or the Journal of Hospital Medicine, or this very magazine, The Hospitalist, or SHM’s numerous educational offerings, chapter events, and SHM national meetings (Converge, Pediatric Hospital Medicine, Leadership Academies, Academic Hospitalist Academy, and more), SHM continues to provide hospitalists with vital tools to help you in your career.

This is also very much a two-way street. If you are reading this, know that without you, our members, our success would not be possible. Your passion and partnership drive us to innovate to meet your needs and those of the patients you serve every day. Thank you for your continued support and inspiration.
 

What could have gone better: Seeing more of you, in person

This is a tough one for me. Everything I worried about going wrong for SHM in 2021 never materialized. A year ago, my fears for SHM were that membership would shrink, finances would dry up, and the SHM staff would leave (by furlough or by choice). Thankfully, membership grew, our finances are in very good shape for any year, let alone a pandemic year, and the staff have remained at SHM and are engaged and dedicated! SHM even received a “Best Place to Work” award from the Philadelphia Business Journal.

Maybe the one regret I have is that we could not do more in-person events. But even there, I think we did better than most. We had some chapter meetings in person, and the October 2021 Leadership Academy hosted 110 hospitalist leaders, in person, at Amelia Island, Fla. That Leadership Academy went off without a hitch, and the early reviews are superb. I am very optimistic about 2022 in-person events!
 

Looking forward: 2022 and beyond

I have no illusions that 2022 is going to be easy. I know that the pandemic will not be gone (even though cases are falling nationwide as of this writing), that our nation will struggle with how to deal with polarization, and the workplace will continue to be redefined. Yet, I can’t help but be optimistic.

The pandemic will end eventually; all pandemics do. My hope is that young leaders will step forward to help our nation work through the divisive challenges, and some of those leaders will even be hospitalists! I also know that our profession is more vital than ever, for both patients and the health care system. We’re even getting ready to celebrate SHM’s 25th anniversary, and we can’t wait to revisit our humble beginnings while looking at the bright future of our society and our field.

I am working on my 2022 “New Year” goals, but you can be pretty sure they will revolve around making the world a better place, investing in people, and being ethical and transparent.

Dr. Howell is the CEO of the Society of Hospital Medicine.

This month marks the end of my first full calendar year as SHM CEO. Over the years, I have made it a habit to take time to reflect during the month of December, assessing the previous year by reviewing what went well and what could have gone better, and how I can grow and change to meet the needs of future challenges. This reflection sets the stage for my personal and professional “New Year” goals.

This year, 2021, is certainly a year deserving of reflection, and I believe 2022 (and beyond) will need ambitious goals made by dedicated leaders, hospitalists included. Here are my thoughts on what went well in 2021 and what I wish went better – from our greater society to our specialty, to SHM.
 

Society (as in the larger society)

What went well: Vaccines

There is a lot to be impressed with in 2021, and for me, at the top of that list are the COVID-19 vaccines. I realize the research for mRNA vaccines started more than 20 years ago, and the most successful mRNA vaccine companies have been around for more than a decade, but to roll out a COVID-19 vaccine in less than a year is still just incredible. To take a disease with a 2% mortality rate for someone like myself and effectively reduce that to near zero is something historians will be writing about for years to come.

What I wish went better: Open dialogue

I can’t remember when we stopped listening to each other, and by that, I mean listening to those who do not think exactly like ourselves. As a kid, I was taught to be careful about discussing topics at social events that could go sideways. That usually involved politics, money, or strong beliefs, but wow – now, that list is much longer. Talking about the weather used to be safe, but not anymore. If I were to show pictures of the recent flooding in Annapolis? There would almost certainly be a debate about climate change. At least we can agree on Ted Lasso as a safe topic.

Our specialty

What went well: Hospitalists are vital

There are many, many professions that deserve “hero” status for their part in taming this pandemic: nurses, doctors, emergency medical services, physical therapists, physician assistants, nurse practitioners, administrators, and more. But in the doctor category, hospitalists are at the top. Along with our emergency department and intensivist colleagues, hospitalists are one of the pillars of the inpatient response to COVID. More than 3.2 million COVID-19 hospitalizations have occurred, according to the Centers for Disease Control and Prevention, with numerous state dashboards showing three-quarters of those are cared for on general medical wards, the domain of hospitalists (for example, see my own state of Maryland’s COVID-19 dashboard: https://coronavirus.maryland.gov).

We’ve always had “two patients” – the patient in the bed and the health care system. Many hospitalists have helped their institutions by building COVID care teams, COVID wards, or in the case of Dr. Mindy Kantsiper, building an entire COVID field hospital in a convention center. Without hospitalists, both patients and the system that serves them would have fared much worse in this pandemic. Hospitalists are vital to patients and the health care system. The end. Period. End of story.
 

What I wish went better: Getting credit

As a profession, we need to be more deliberate about getting credit for the fantastic work we have done to care for COVID-19 patients, as well as inpatients in general. SHM can and must focus more on how to highlight the great work hospitalists have done and will continue to do. A greater understanding by the health care industry – as well as the general public – regarding the important role we play for patient care will help add autonomy in our profession, which in turn adds to resilience during these challenging times.

SHM

What went well: Membership grew

This is the one thing that we at SHM – and I personally – are most proud of. SHM is a membership society; it is the single most important metric for me personally. If physicians aren’t joining, then we are not meeting our core mission to provide value to hospitalists. My sense is the services SHM provides to hospitalists continue to be of value – even during these strenuous times of the pandemic when we had to be physically distant.

Whether it’s our Government Relations Department advocating for hospitalists in Washington, or the Journal of Hospital Medicine, or this very magazine, The Hospitalist, or SHM’s numerous educational offerings, chapter events, and SHM national meetings (Converge, Pediatric Hospital Medicine, Leadership Academies, Academic Hospitalist Academy, and more), SHM continues to provide hospitalists with vital tools to help you in your career.

This is also very much a two-way street. If you are reading this, know that without you, our members, our success would not be possible. Your passion and partnership drive us to innovate to meet your needs and those of the patients you serve every day. Thank you for your continued support and inspiration.
 

What could have gone better: Seeing more of you, in person

This is a tough one for me. Everything I worried about going wrong for SHM in 2021 never materialized. A year ago, my fears for SHM were that membership would shrink, finances would dry up, and the SHM staff would leave (by furlough or by choice). Thankfully, membership grew, our finances are in very good shape for any year, let alone a pandemic year, and the staff have remained at SHM and are engaged and dedicated! SHM even received a “Best Place to Work” award from the Philadelphia Business Journal.

Maybe the one regret I have is that we could not do more in-person events. But even there, I think we did better than most. We had some chapter meetings in person, and the October 2021 Leadership Academy hosted 110 hospitalist leaders, in person, at Amelia Island, Fla. That Leadership Academy went off without a hitch, and the early reviews are superb. I am very optimistic about 2022 in-person events!
 

Looking forward: 2022 and beyond

I have no illusions that 2022 is going to be easy. I know that the pandemic will not be gone (even though cases are falling nationwide as of this writing), that our nation will struggle with how to deal with polarization, and the workplace will continue to be redefined. Yet, I can’t help but be optimistic.

The pandemic will end eventually; all pandemics do. My hope is that young leaders will step forward to help our nation work through the divisive challenges, and some of those leaders will even be hospitalists! I also know that our profession is more vital than ever, for both patients and the health care system. We’re even getting ready to celebrate SHM’s 25th anniversary, and we can’t wait to revisit our humble beginnings while looking at the bright future of our society and our field.

I am working on my 2022 “New Year” goals, but you can be pretty sure they will revolve around making the world a better place, investing in people, and being ethical and transparent.

Dr. Howell is the CEO of the Society of Hospital Medicine.

This month marks the end of my first full calendar year as SHM CEO. Over the years, I have made it a habit to take time to reflect during the month of December, assessing the previous year by reviewing what went well and what could have gone better, and how I can grow and change to meet the needs of future challenges. This reflection sets the stage for my personal and professional “New Year” goals.

This year, 2021, is certainly a year deserving of reflection, and I believe 2022 (and beyond) will need ambitious goals made by dedicated leaders, hospitalists included. Here are my thoughts on what went well in 2021 and what I wish went better – from our greater society to our specialty, to SHM.
 

Society (as in the larger society)

What went well: Vaccines

There is a lot to be impressed with in 2021, and for me, at the top of that list are the COVID-19 vaccines. I realize the research for mRNA vaccines started more than 20 years ago, and the most successful mRNA vaccine companies have been around for more than a decade, but to roll out a COVID-19 vaccine in less than a year is still just incredible. To take a disease with a 2% mortality rate for someone like myself and effectively reduce that to near zero is something historians will be writing about for years to come.

What I wish went better: Open dialogue

I can’t remember when we stopped listening to each other, and by that, I mean listening to those who do not think exactly like ourselves. As a kid, I was taught to be careful about discussing topics at social events that could go sideways. That usually involved politics, money, or strong beliefs, but wow – now, that list is much longer. Talking about the weather used to be safe, but not anymore. If I were to show pictures of the recent flooding in Annapolis? There would almost certainly be a debate about climate change. At least we can agree on Ted Lasso as a safe topic.

Our specialty

What went well: Hospitalists are vital

There are many, many professions that deserve “hero” status for their part in taming this pandemic: nurses, doctors, emergency medical services, physical therapists, physician assistants, nurse practitioners, administrators, and more. But in the doctor category, hospitalists are at the top. Along with our emergency department and intensivist colleagues, hospitalists are one of the pillars of the inpatient response to COVID. More than 3.2 million COVID-19 hospitalizations have occurred, according to the Centers for Disease Control and Prevention, with numerous state dashboards showing three-quarters of those are cared for on general medical wards, the domain of hospitalists (for example, see my own state of Maryland’s COVID-19 dashboard: https://coronavirus.maryland.gov).

We’ve always had “two patients” – the patient in the bed and the health care system. Many hospitalists have helped their institutions by building COVID care teams, COVID wards, or in the case of Dr. Mindy Kantsiper, building an entire COVID field hospital in a convention center. Without hospitalists, both patients and the system that serves them would have fared much worse in this pandemic. Hospitalists are vital to patients and the health care system. The end. Period. End of story.
 

What I wish went better: Getting credit

As a profession, we need to be more deliberate about getting credit for the fantastic work we have done to care for COVID-19 patients, as well as inpatients in general. SHM can and must focus more on how to highlight the great work hospitalists have done and will continue to do. A greater understanding by the health care industry – as well as the general public – regarding the important role we play for patient care will help add autonomy in our profession, which in turn adds to resilience during these challenging times.

SHM

What went well: Membership grew

This is the one thing that we at SHM – and I personally – are most proud of. SHM is a membership society; it is the single most important metric for me personally. If physicians aren’t joining, then we are not meeting our core mission to provide value to hospitalists. My sense is the services SHM provides to hospitalists continue to be of value – even during these strenuous times of the pandemic when we had to be physically distant.

Whether it’s our Government Relations Department advocating for hospitalists in Washington, or the Journal of Hospital Medicine, or this very magazine, The Hospitalist, or SHM’s numerous educational offerings, chapter events, and SHM national meetings (Converge, Pediatric Hospital Medicine, Leadership Academies, Academic Hospitalist Academy, and more), SHM continues to provide hospitalists with vital tools to help you in your career.

This is also very much a two-way street. If you are reading this, know that without you, our members, our success would not be possible. Your passion and partnership drive us to innovate to meet your needs and those of the patients you serve every day. Thank you for your continued support and inspiration.
 

What could have gone better: Seeing more of you, in person

This is a tough one for me. Everything I worried about going wrong for SHM in 2021 never materialized. A year ago, my fears for SHM were that membership would shrink, finances would dry up, and the SHM staff would leave (by furlough or by choice). Thankfully, membership grew, our finances are in very good shape for any year, let alone a pandemic year, and the staff have remained at SHM and are engaged and dedicated! SHM even received a “Best Place to Work” award from the Philadelphia Business Journal.

Maybe the one regret I have is that we could not do more in-person events. But even there, I think we did better than most. We had some chapter meetings in person, and the October 2021 Leadership Academy hosted 110 hospitalist leaders, in person, at Amelia Island, Fla. That Leadership Academy went off without a hitch, and the early reviews are superb. I am very optimistic about 2022 in-person events!
 

Looking forward: 2022 and beyond

I have no illusions that 2022 is going to be easy. I know that the pandemic will not be gone (even though cases are falling nationwide as of this writing), that our nation will struggle with how to deal with polarization, and the workplace will continue to be redefined. Yet, I can’t help but be optimistic.

The pandemic will end eventually; all pandemics do. My hope is that young leaders will step forward to help our nation work through the divisive challenges, and some of those leaders will even be hospitalists! I also know that our profession is more vital than ever, for both patients and the health care system. We’re even getting ready to celebrate SHM’s 25th anniversary, and we can’t wait to revisit our humble beginnings while looking at the bright future of our society and our field.

I am working on my 2022 “New Year” goals, but you can be pretty sure they will revolve around making the world a better place, investing in people, and being ethical and transparent.

Dr. Howell is the CEO of the Society of Hospital Medicine.

Clinicians should approach decisions regarding coronary revascularization based on clinical indications without an eye toward sex, race, or ethnicity, advises a joint clinical practice guideline released Dec. 8 by the American Heart Association and American College of Cardiology.

The new class 1 recommendation leads off the 109-page document and reflects evidence demonstrating that revascularization is equally beneficial for all patients. Still, studies show that women and non-White patients are less likely to receive reperfusion therapy or revascularization.

“This was extremely important to all the committee members because of all of the disparities that have been documented not only in diagnosis but [in] the care provided to underrepresented minorities, women, and other ethnic groups,” said Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair.  

“We wanted to make it clear right at the beginning of the document that these guidelines apply to everyone, and we want it to be known that care should be the same for everyone,” she said in an interview.

The guideline was simultaneously published Dec. 9, 2021, in the journal  Circulation  and the  Journal of the American College of Cardiology. 

It updates and consolidates the ACC/AHA 2011 coronary artery bypass surgery (CABG) guideline and the ACC/AHA/Society for Cardiovascular Angiography and Interventions 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The new document emphasizes in a class 1 recommendation the importance of the multidisciplinary heart team in patients with coronary artery disease (CAD) where the best treatment strategy is unclear. But it also stresses that treatment decisions should be patient centered – taking into account patient preferences and goals, cultural beliefs, health literacy, and social determinants of cardiovascular health – and made in collaboration with the patient’s support system.

“Oftentimes we recommend a strategy of revascularization that may not be what the patient wants or hasn’t taken into account the patient’s preferences and also the family members,” Dr. Lawson said. “So we felt that was very important.”

Patients should also be provided with available evidence for various treatment options, including risks and benefits of each option, for informed consent. The two new class 1 recommendations are highlighted in a figure illustrating the shared decision-making algorithm that, by design, features a female clinician and Black patient.

“We spent 2 years debating the best revascularization strategies and we’re considered experts in the field – but when we talk to our patients, they really don’t know the benefits and risks,” she said. “In order to translate it to the layperson in basic terms, it’s important to say, ‘If you choose this option, you will likely live longer’ rather than using the jargon.”
 

DAPT, staged PCI, stable IHD

Among the top 10 take-home messages highlighted by the authors is a 2a recommendation that 1-3 months of dual antiplatelet therapy (DAPT) after PCI with a transition to P2Y12 inhibitor monotherapy is “reasonable” in selected patients to reduce the risk of bleeding events. Previous recommendations called for 6 or 12 months of DAPT.

enot-poloskun/Getty Images

“We really respect all of the clinical trials that came out showing that a shorter duration of DAPT is not inferior in terms of ischemic events but less bleeding, yet I don’t know how many clinicians are actually just using 3 months of DAPT followed by P2Y12 monotherapy,” guideline committee vice chair Jacqueline Tamis-Holland, MD, professor of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an interview. “So while it’s not a big, glaring giant recommendation, I think it will change a lot of practice.”

Similarly, she suggested that practice may shift as a result of a class 1 recommendation for staged PCI of a significantly stenosed nonculprit artery to reduce the risk for death or MI in selected hemodynamically stable patients presenting with ST-segment elevation MI and multivessel disease. “When you survey physicians, 75% of them do staged PCI but I think there will probably be more of an approach to staged PCI, as opposed to doing multivessel PCI at the time of primary PCI.”

Newer evidence from meta-analyses and the landmark ISCHEMIA trial showing no advantage of CABG over medical therapy in stable ischemic heart disease is reflected in a new class 2b recommendation – downgraded from class 1 in 2011 – that CABG “may be reasonable” to improve survival in stable patients with triple-vessel CAD.

The writing committee concluded that the ability of PCI to improve survival, compared with medical therapy in multivessel CAD “remains uncertain.”

Other recommendations likely to be of interest are that the radial artery is preferred, after the left internal mammary artery, as a surgical revascularization conduit over use of a saphenous vein conduit. Benefits include superior patency, fewer adverse cardiac events, and improved survival, the committee noted.

The radial artery is also recommended (class 1) in patients undergoing PCI who have acute coronary syndromes or stable ischemic heart disease to reduce bleeding and vascular complications compared with a femoral approach.

“Having both new radial recommendations sort of makes a bit of tension because the interventionalist is going to want to use the radial artery, but also the surgeon is too,” observed Dr. Tamis-Holland. “We see that in our own practice, so we try to have a collaborative approach to the patient to say: ‘Maybe do the cardiac cath in the dominant radial and then we can use the nondominant radial for a bypass conduit,’ but using both for each revascularization strategy will benefit the patient.

“So, we just have to remember that we’re going to talk together as a heart team and try to make the best decisions for each patient.”

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

Clinicians should approach decisions regarding coronary revascularization based on clinical indications without an eye toward sex, race, or ethnicity, advises a joint clinical practice guideline released Dec. 8 by the American Heart Association and American College of Cardiology.

The new class 1 recommendation leads off the 109-page document and reflects evidence demonstrating that revascularization is equally beneficial for all patients. Still, studies show that women and non-White patients are less likely to receive reperfusion therapy or revascularization.

“This was extremely important to all the committee members because of all of the disparities that have been documented not only in diagnosis but [in] the care provided to underrepresented minorities, women, and other ethnic groups,” said Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair.  

“We wanted to make it clear right at the beginning of the document that these guidelines apply to everyone, and we want it to be known that care should be the same for everyone,” she said in an interview.

The guideline was simultaneously published Dec. 9, 2021, in the journal  Circulation  and the  Journal of the American College of Cardiology. 

It updates and consolidates the ACC/AHA 2011 coronary artery bypass surgery (CABG) guideline and the ACC/AHA/Society for Cardiovascular Angiography and Interventions 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The new document emphasizes in a class 1 recommendation the importance of the multidisciplinary heart team in patients with coronary artery disease (CAD) where the best treatment strategy is unclear. But it also stresses that treatment decisions should be patient centered – taking into account patient preferences and goals, cultural beliefs, health literacy, and social determinants of cardiovascular health – and made in collaboration with the patient’s support system.

“Oftentimes we recommend a strategy of revascularization that may not be what the patient wants or hasn’t taken into account the patient’s preferences and also the family members,” Dr. Lawson said. “So we felt that was very important.”

Patients should also be provided with available evidence for various treatment options, including risks and benefits of each option, for informed consent. The two new class 1 recommendations are highlighted in a figure illustrating the shared decision-making algorithm that, by design, features a female clinician and Black patient.

“We spent 2 years debating the best revascularization strategies and we’re considered experts in the field – but when we talk to our patients, they really don’t know the benefits and risks,” she said. “In order to translate it to the layperson in basic terms, it’s important to say, ‘If you choose this option, you will likely live longer’ rather than using the jargon.”
 

DAPT, staged PCI, stable IHD

Among the top 10 take-home messages highlighted by the authors is a 2a recommendation that 1-3 months of dual antiplatelet therapy (DAPT) after PCI with a transition to P2Y12 inhibitor monotherapy is “reasonable” in selected patients to reduce the risk of bleeding events. Previous recommendations called for 6 or 12 months of DAPT.

enot-poloskun/Getty Images

“We really respect all of the clinical trials that came out showing that a shorter duration of DAPT is not inferior in terms of ischemic events but less bleeding, yet I don’t know how many clinicians are actually just using 3 months of DAPT followed by P2Y12 monotherapy,” guideline committee vice chair Jacqueline Tamis-Holland, MD, professor of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an interview. “So while it’s not a big, glaring giant recommendation, I think it will change a lot of practice.”

Similarly, she suggested that practice may shift as a result of a class 1 recommendation for staged PCI of a significantly stenosed nonculprit artery to reduce the risk for death or MI in selected hemodynamically stable patients presenting with ST-segment elevation MI and multivessel disease. “When you survey physicians, 75% of them do staged PCI but I think there will probably be more of an approach to staged PCI, as opposed to doing multivessel PCI at the time of primary PCI.”

Newer evidence from meta-analyses and the landmark ISCHEMIA trial showing no advantage of CABG over medical therapy in stable ischemic heart disease is reflected in a new class 2b recommendation – downgraded from class 1 in 2011 – that CABG “may be reasonable” to improve survival in stable patients with triple-vessel CAD.

The writing committee concluded that the ability of PCI to improve survival, compared with medical therapy in multivessel CAD “remains uncertain.”

Other recommendations likely to be of interest are that the radial artery is preferred, after the left internal mammary artery, as a surgical revascularization conduit over use of a saphenous vein conduit. Benefits include superior patency, fewer adverse cardiac events, and improved survival, the committee noted.

The radial artery is also recommended (class 1) in patients undergoing PCI who have acute coronary syndromes or stable ischemic heart disease to reduce bleeding and vascular complications compared with a femoral approach.

“Having both new radial recommendations sort of makes a bit of tension because the interventionalist is going to want to use the radial artery, but also the surgeon is too,” observed Dr. Tamis-Holland. “We see that in our own practice, so we try to have a collaborative approach to the patient to say: ‘Maybe do the cardiac cath in the dominant radial and then we can use the nondominant radial for a bypass conduit,’ but using both for each revascularization strategy will benefit the patient.

“So, we just have to remember that we’re going to talk together as a heart team and try to make the best decisions for each patient.”

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

Clinicians should approach decisions regarding coronary revascularization based on clinical indications without an eye toward sex, race, or ethnicity, advises a joint clinical practice guideline released Dec. 8 by the American Heart Association and American College of Cardiology.

The new class 1 recommendation leads off the 109-page document and reflects evidence demonstrating that revascularization is equally beneficial for all patients. Still, studies show that women and non-White patients are less likely to receive reperfusion therapy or revascularization.

“This was extremely important to all the committee members because of all of the disparities that have been documented not only in diagnosis but [in] the care provided to underrepresented minorities, women, and other ethnic groups,” said Jennifer S. Lawton, MD, chief of cardiac surgery at Johns Hopkins University, Baltimore, and guideline writing committee chair.  

“We wanted to make it clear right at the beginning of the document that these guidelines apply to everyone, and we want it to be known that care should be the same for everyone,” she said in an interview.

The guideline was simultaneously published Dec. 9, 2021, in the journal  Circulation  and the  Journal of the American College of Cardiology. 

It updates and consolidates the ACC/AHA 2011 coronary artery bypass surgery (CABG) guideline and the ACC/AHA/Society for Cardiovascular Angiography and Interventions 2011 and 2015 percutaneous coronary intervention (PCI) guidelines.

The new document emphasizes in a class 1 recommendation the importance of the multidisciplinary heart team in patients with coronary artery disease (CAD) where the best treatment strategy is unclear. But it also stresses that treatment decisions should be patient centered – taking into account patient preferences and goals, cultural beliefs, health literacy, and social determinants of cardiovascular health – and made in collaboration with the patient’s support system.

“Oftentimes we recommend a strategy of revascularization that may not be what the patient wants or hasn’t taken into account the patient’s preferences and also the family members,” Dr. Lawson said. “So we felt that was very important.”

Patients should also be provided with available evidence for various treatment options, including risks and benefits of each option, for informed consent. The two new class 1 recommendations are highlighted in a figure illustrating the shared decision-making algorithm that, by design, features a female clinician and Black patient.

“We spent 2 years debating the best revascularization strategies and we’re considered experts in the field – but when we talk to our patients, they really don’t know the benefits and risks,” she said. “In order to translate it to the layperson in basic terms, it’s important to say, ‘If you choose this option, you will likely live longer’ rather than using the jargon.”
 

DAPT, staged PCI, stable IHD

Among the top 10 take-home messages highlighted by the authors is a 2a recommendation that 1-3 months of dual antiplatelet therapy (DAPT) after PCI with a transition to P2Y12 inhibitor monotherapy is “reasonable” in selected patients to reduce the risk of bleeding events. Previous recommendations called for 6 or 12 months of DAPT.

enot-poloskun/Getty Images

“We really respect all of the clinical trials that came out showing that a shorter duration of DAPT is not inferior in terms of ischemic events but less bleeding, yet I don’t know how many clinicians are actually just using 3 months of DAPT followed by P2Y12 monotherapy,” guideline committee vice chair Jacqueline Tamis-Holland, MD, professor of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an interview. “So while it’s not a big, glaring giant recommendation, I think it will change a lot of practice.”

Similarly, she suggested that practice may shift as a result of a class 1 recommendation for staged PCI of a significantly stenosed nonculprit artery to reduce the risk for death or MI in selected hemodynamically stable patients presenting with ST-segment elevation MI and multivessel disease. “When you survey physicians, 75% of them do staged PCI but I think there will probably be more of an approach to staged PCI, as opposed to doing multivessel PCI at the time of primary PCI.”

Newer evidence from meta-analyses and the landmark ISCHEMIA trial showing no advantage of CABG over medical therapy in stable ischemic heart disease is reflected in a new class 2b recommendation – downgraded from class 1 in 2011 – that CABG “may be reasonable” to improve survival in stable patients with triple-vessel CAD.

The writing committee concluded that the ability of PCI to improve survival, compared with medical therapy in multivessel CAD “remains uncertain.”

Other recommendations likely to be of interest are that the radial artery is preferred, after the left internal mammary artery, as a surgical revascularization conduit over use of a saphenous vein conduit. Benefits include superior patency, fewer adverse cardiac events, and improved survival, the committee noted.

The radial artery is also recommended (class 1) in patients undergoing PCI who have acute coronary syndromes or stable ischemic heart disease to reduce bleeding and vascular complications compared with a femoral approach.

“Having both new radial recommendations sort of makes a bit of tension because the interventionalist is going to want to use the radial artery, but also the surgeon is too,” observed Dr. Tamis-Holland. “We see that in our own practice, so we try to have a collaborative approach to the patient to say: ‘Maybe do the cardiac cath in the dominant radial and then we can use the nondominant radial for a bypass conduit,’ but using both for each revascularization strategy will benefit the patient.

“So, we just have to remember that we’re going to talk together as a heart team and try to make the best decisions for each patient.”

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

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

The thresholds for genomic instability scores in triple-negative breast cancer (TNBC) are similar to those in ovarian cancer but different from in estrogen receptor–positive (ER+) breast cancer, which could eventually be used to help guide treatment decisions, suggests an analysis of trial data.

More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.

The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.

“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.

This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”

The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.

Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.

“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”

He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.

“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.

He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.

“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”

Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”

“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.

She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”

Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”

She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.

“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.

“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.

Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.

The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.

As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.

They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.

GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.

The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10^–5) and TNBC (P = 2.1 x 10^–4).

The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.

The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.

Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.

As the lesion was growing, getting more violaceous and indurated, a biopsy was performed. The biopsy showed multiple discrete lobules of dermal capillaries with slight extension into the superficial subcutis. Capillary lobules demonstrate the “cannonball-like” architecture often associated with tufted angioma, and some lobules showed bulging into adjacent thin-walled vessels. Spindled endothelial cells lining slit-like vessels were present in the mid dermis, although this comprises a minority of the lesion. The majority of the subcutis was uninvolved. The findings are overall most consistent with a tufted angioma.

Kaposiform hemangioendothelioma (KHE) has been considered given the presence of occasional slit-like vascular spaces; however, the lesion is predominantly superficial and therefore the lesion is best classified as tufted angioma. GLUT–1 staining was negative.

At the time of biopsy, blood work was ordered, which showed a normal complete blood count with normal number of platelets, slightly elevated D-dimer, and slightly low fibrinogen. Several repeat blood counts and coagulation tests once a week for a few weeks revealed no changes.

The patient was started on aspirin at a dose of 5 mg/kg per day. After a week on the medication the lesion was starting to get smaller and less red.

Tufted angiomas are a rare type of vascular tumor within the spectrum of kaposiform hemangioendotheliomas. Most cases present within the first year of life; some occur at birth. They usually present as papules, plaques, or erythematous, violaceous indurated nodules on the face, neck, trunk, and extremities. The lesions can also be present with hyperhidrosis and hypertrichosis. Clinically, the lesions will have to be differentiated from other vascular tumors such as infantile hemangiomas, congenital hemangiomas, and Kaposi’s sarcoma, as well as subcutaneous fat necrosis of the newborn, cellulitis, and nonaccidental trauma.

Pathogenesis of tufted angiomas is poorly understood. A recent case report found a somatic mutation on GNA14.This protein regulates Ras activity and modulates endothelial cell permeability and migration in response to FGF2 and VEGFA. The p.205L mutation causes activation of GNA14, which upregulates pERK-MAPK pathway, suggesting MAPK inhibition as a potential target for therapy. Clinically, tufted angioma can present in three patterns: uncomplicated tufted angioma (most common type); tufted angioma without thrombocytopenia but with chronic coagulopathy, as it was seen in our patient; and tufted angioma associated with Kasabach-Merritt phenomenon (KMP). KMP is characterized by thrombocytopenia in association with microangiopathic hemolytic anemia, consumptive coagulopathy, and enlarging vascular tumor. Treatment of uncomplicated tufted angioma will depend on symptomatology, size, and location of the lesion. Smaller lesions in noncosmetically sensitive areas can be treated with surgical excision. Cases that are not amenable to excision can be treated with aspirin. There are also reports of response to topical modalities including tacrolimus and timolol. For complicated cases associated with KMP, sirolimus, systemic corticosteroids, ticlopidine, interferon, or vincristine are recommended. Some lesions may demonstrate spontaneous regression.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.

References

Cohen S et al. Dermatol Online J. 2019 Sep 15;25(9):13030/qt6pv254mc.

Lim YH et al. Pediatr Dermatol. 2019 Nov;36(6):963-4.

Prasuna A, Rao PN. Indian Dermatol Online J. 2015;6:266-8.

As the lesion was growing, getting more violaceous and indurated, a biopsy was performed. The biopsy showed multiple discrete lobules of dermal capillaries with slight extension into the superficial subcutis. Capillary lobules demonstrate the “cannonball-like” architecture often associated with tufted angioma, and some lobules showed bulging into adjacent thin-walled vessels. Spindled endothelial cells lining slit-like vessels were present in the mid dermis, although this comprises a minority of the lesion. The majority of the subcutis was uninvolved. The findings are overall most consistent with a tufted angioma.

Kaposiform hemangioendothelioma (KHE) has been considered given the presence of occasional slit-like vascular spaces; however, the lesion is predominantly superficial and therefore the lesion is best classified as tufted angioma. GLUT–1 staining was negative.

At the time of biopsy, blood work was ordered, which showed a normal complete blood count with normal number of platelets, slightly elevated D-dimer, and slightly low fibrinogen. Several repeat blood counts and coagulation tests once a week for a few weeks revealed no changes.

The patient was started on aspirin at a dose of 5 mg/kg per day. After a week on the medication the lesion was starting to get smaller and less red.

Tufted angiomas are a rare type of vascular tumor within the spectrum of kaposiform hemangioendotheliomas. Most cases present within the first year of life; some occur at birth. They usually present as papules, plaques, or erythematous, violaceous indurated nodules on the face, neck, trunk, and extremities. The lesions can also be present with hyperhidrosis and hypertrichosis. Clinically, the lesions will have to be differentiated from other vascular tumors such as infantile hemangiomas, congenital hemangiomas, and Kaposi’s sarcoma, as well as subcutaneous fat necrosis of the newborn, cellulitis, and nonaccidental trauma.

Pathogenesis of tufted angiomas is poorly understood. A recent case report found a somatic mutation on GNA14.This protein regulates Ras activity and modulates endothelial cell permeability and migration in response to FGF2 and VEGFA. The p.205L mutation causes activation of GNA14, which upregulates pERK-MAPK pathway, suggesting MAPK inhibition as a potential target for therapy. Clinically, tufted angioma can present in three patterns: uncomplicated tufted angioma (most common type); tufted angioma without thrombocytopenia but with chronic coagulopathy, as it was seen in our patient; and tufted angioma associated with Kasabach-Merritt phenomenon (KMP). KMP is characterized by thrombocytopenia in association with microangiopathic hemolytic anemia, consumptive coagulopathy, and enlarging vascular tumor. Treatment of uncomplicated tufted angioma will depend on symptomatology, size, and location of the lesion. Smaller lesions in noncosmetically sensitive areas can be treated with surgical excision. Cases that are not amenable to excision can be treated with aspirin. There are also reports of response to topical modalities including tacrolimus and timolol. For complicated cases associated with KMP, sirolimus, systemic corticosteroids, ticlopidine, interferon, or vincristine are recommended. Some lesions may demonstrate spontaneous regression.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.

References

Cohen S et al. Dermatol Online J. 2019 Sep 15;25(9):13030/qt6pv254mc.

Lim YH et al. Pediatr Dermatol. 2019 Nov;36(6):963-4.

Prasuna A, Rao PN. Indian Dermatol Online J. 2015;6:266-8.

As the lesion was growing, getting more violaceous and indurated, a biopsy was performed. The biopsy showed multiple discrete lobules of dermal capillaries with slight extension into the superficial subcutis. Capillary lobules demonstrate the “cannonball-like” architecture often associated with tufted angioma, and some lobules showed bulging into adjacent thin-walled vessels. Spindled endothelial cells lining slit-like vessels were present in the mid dermis, although this comprises a minority of the lesion. The majority of the subcutis was uninvolved. The findings are overall most consistent with a tufted angioma.

Kaposiform hemangioendothelioma (KHE) has been considered given the presence of occasional slit-like vascular spaces; however, the lesion is predominantly superficial and therefore the lesion is best classified as tufted angioma. GLUT–1 staining was negative.

At the time of biopsy, blood work was ordered, which showed a normal complete blood count with normal number of platelets, slightly elevated D-dimer, and slightly low fibrinogen. Several repeat blood counts and coagulation tests once a week for a few weeks revealed no changes.

The patient was started on aspirin at a dose of 5 mg/kg per day. After a week on the medication the lesion was starting to get smaller and less red.

Tufted angiomas are a rare type of vascular tumor within the spectrum of kaposiform hemangioendotheliomas. Most cases present within the first year of life; some occur at birth. They usually present as papules, plaques, or erythematous, violaceous indurated nodules on the face, neck, trunk, and extremities. The lesions can also be present with hyperhidrosis and hypertrichosis. Clinically, the lesions will have to be differentiated from other vascular tumors such as infantile hemangiomas, congenital hemangiomas, and Kaposi’s sarcoma, as well as subcutaneous fat necrosis of the newborn, cellulitis, and nonaccidental trauma.

Pathogenesis of tufted angiomas is poorly understood. A recent case report found a somatic mutation on GNA14.This protein regulates Ras activity and modulates endothelial cell permeability and migration in response to FGF2 and VEGFA. The p.205L mutation causes activation of GNA14, which upregulates pERK-MAPK pathway, suggesting MAPK inhibition as a potential target for therapy. Clinically, tufted angioma can present in three patterns: uncomplicated tufted angioma (most common type); tufted angioma without thrombocytopenia but with chronic coagulopathy, as it was seen in our patient; and tufted angioma associated with Kasabach-Merritt phenomenon (KMP). KMP is characterized by thrombocytopenia in association with microangiopathic hemolytic anemia, consumptive coagulopathy, and enlarging vascular tumor. Treatment of uncomplicated tufted angioma will depend on symptomatology, size, and location of the lesion. Smaller lesions in noncosmetically sensitive areas can be treated with surgical excision. Cases that are not amenable to excision can be treated with aspirin. There are also reports of response to topical modalities including tacrolimus and timolol. For complicated cases associated with KMP, sirolimus, systemic corticosteroids, ticlopidine, interferon, or vincristine are recommended. Some lesions may demonstrate spontaneous regression.

Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego.

References

Cohen S et al. Dermatol Online J. 2019 Sep 15;25(9):13030/qt6pv254mc.

Lim YH et al. Pediatr Dermatol. 2019 Nov;36(6):963-4.

Prasuna A, Rao PN. Indian Dermatol Online J. 2015;6:266-8.

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

[email protected]

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

[email protected]

Meeting the treatment needs of the nearly 50% of women with metastatic breast cancer in British Columbia who could benefit from continued access to HER2 suppression would cost the province at least $68,000 more per patient, given the changing treatment landscape, an analysis of outcomes and pharmacy data suggests.

The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.

Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.

Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.

During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.

To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.

Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.

“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”

At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.

The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.

The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.

Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.

The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.

The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.

“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.

A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.

[email protected]

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Background: DOACs have largely replaced VKAs as first-line therapy for venous thromboembolism in patients with adequate renal function. However, there is concern in APS that DOACs may have higher rates of recurrent thrombosis than VKAs when treating thromboembolism.

The DOAC arm was not proven to be noninferior with respect to the primary outcome of thrombotic events. The higher risk of stroke in this group suggests the need for caution in using DOACs in this population.

Bottom line: DOACs have a higher risk of stroke than VKAs in patients with APS without a significant difference in rate of a major bleed.

Citation: Ordi-Ros J et. al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome. Ann Intern Med. 2019;171(10):685-94. doi: 10.7326/M19-0291.

Dr. Portnoy is a hospitalist in the Division of Hospital Medicine, Mount Sinai Health System, New York.

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE E1² lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B Complex vitamins

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Continue to: Vitamin B2...

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6...

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12...

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Antioxidants

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Continue to: Vitamin A...

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D...

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure
Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Multivitamins

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²
 

Summary

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE E1² lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B Complex vitamins

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Continue to: Vitamin B2...

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6...

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12...

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Antioxidants

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Continue to: Vitamin A...

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D...

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure
Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Multivitamins

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²
 

Summary

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE E1² lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B Complex vitamins

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Continue to: Vitamin B2...

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6...

Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12...

Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Antioxidants

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Continue to: Vitamin A...

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D...

Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure
Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Multivitamins

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²
 

Summary

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.

A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.

“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.

Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.

There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.

To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.

They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).

Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.

The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.

The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.