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The multitasking myth
, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.
According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.
On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.
It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.
Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .
So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?
The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.
Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.
Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?
In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”
If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].
, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.
According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.
On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.
It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.
Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .
So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?
The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.
Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.
Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?
In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”
If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].
, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.
According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.
On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.
It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.
Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .
So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?
The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.
Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.
Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?
In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”
If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].
Zuranolone: A novel postpartum depression treatment, with lingering questions
Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.
That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?
Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.
Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.
Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.
It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
Where zuranolone fits into the treatment algorithm for severe PPD
Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:
Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.
Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.
Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?
Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.
The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.
Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that , along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].
Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.
That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?
Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.
Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.
Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.
It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
Where zuranolone fits into the treatment algorithm for severe PPD
Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:
Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.
Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.
Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?
Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.
The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.
Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that , along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].
Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.
That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?
Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.
Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.
Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.
It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
Where zuranolone fits into the treatment algorithm for severe PPD
Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:
Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.
Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.
Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?
Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.
The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.
Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that , along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].
Do you P.U.I.?
In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.
Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.
My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.
When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.
So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?
Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?
Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?
Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?
Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.
In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.
Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.
My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.
When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.
So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?
Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?
Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?
Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?
Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.
In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.
Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.
My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.
When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.
So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?
Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?
Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?
Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?
Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.
In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Noteworthy advances in treatment and management of IBD
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
AT DDW 2023
Low-dose colchicine for ASCVD: Your questions answered
This transcript has been edited for clarity.
Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.
who’s been at the forefront of research into anti-inflammatory therapeutics.
Lifestyle lipid-lowering paramount
Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?
Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.
I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.
Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.
The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
Inflammatory pathway
Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?
Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.
Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.
The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.
It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
When to start colchicine, and in whom?
Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.
At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?
Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.
In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.
I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.
There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.
Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.
In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.
Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.
In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?
Colchicine safety and contraindications
Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.
One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.
Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.
Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?
Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.
I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.
The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
Inpatient vs. outpatient initiation
Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?
Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.
Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.
Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.
I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.
Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.
Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.
Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.
This transcript has been edited for clarity.
Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.
who’s been at the forefront of research into anti-inflammatory therapeutics.
Lifestyle lipid-lowering paramount
Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?
Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.
I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.
Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.
The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
Inflammatory pathway
Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?
Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.
Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.
The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.
It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
When to start colchicine, and in whom?
Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.
At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?
Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.
In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.
I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.
There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.
Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.
In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.
Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.
In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?
Colchicine safety and contraindications
Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.
One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.
Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.
Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?
Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.
I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.
The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
Inpatient vs. outpatient initiation
Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?
Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.
Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.
Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.
I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.
Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.
Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.
Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.
This transcript has been edited for clarity.
Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.
who’s been at the forefront of research into anti-inflammatory therapeutics.
Lifestyle lipid-lowering paramount
Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?
Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.
I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.
Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.
The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
Inflammatory pathway
Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?
Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.
Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.
The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.
It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
When to start colchicine, and in whom?
Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.
At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?
Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.
In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.
I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.
There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.
Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.
In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.
Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.
In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?
Colchicine safety and contraindications
Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.
One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.
Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.
Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?
Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.
I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.
The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
Inpatient vs. outpatient initiation
Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?
Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.
Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.
Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.
I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.
Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.
Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.
Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.
My favorite iron pearls
A 45-year-old women presents for evaluation of fatigue. She has been tired for the past 6 months. She has had no problems with sleep and no other new symptoms. Her physical exam is unremarkable. Her Patient Health Questionnaire–9 score is 4. Lab results are as follows: hemoglobin, 13 g/dL; hematocrit, 39%; mean corpuscular volume, 90 fL; blood urea nitrogen, 10 mg/dL; Cr, 1.0 mg/dL; AST, 20 IU/L; ALT, 15 IU/L; ferritin, 35 mcg/mL; thyroid-stimulating hormone, 3.5 mIU/L.
What would you recommend?
A. Sertraline
B. Sleep study
C. Iron supplementation
I would treat this patient with iron. Verdon and colleagues conducted a randomized, double-blind placebo-controlled trial of iron treatment in nonanemic women.1 The women who received iron had a much greater reduction in fatigue score, compared with the women who did not (P < .004). Only women with ferritin levels less than 50 mcg/L benefited. Houston and colleagues performed a systematic review of the literature of iron supplementation for fatigue and concluded that iron should be considered for treatment of fatigue in nonanemic women.2 The key number for benefit was a ferritin level less than 50 mcg/L.
Hair thinning is a common concern for many women. Does iron deficiency have a possible role in this problem? A number of studies have correlated low ferritin levels with hair loss.3 There is less clear evidence of iron treatment being effective. Hard studied 140 women with diffuse hair loss, and found 19% had iron deficiency without anemia.4 All patients with iron deficiency were treated with oral iron and in all patients hair loss ceased, and hair regrowth occurred. The target ferritin goal for treatment is greater than 40 mcg/L.5
Iron deficiency is an important trigger for restless leg syndrome (RLS). All patients who present with RLS should have ferritin checked, and appropriate evaluation for the cause of iron deficiency if ferritin levels are low. Allen and colleagues published clinical practice guidelines for iron treatment of RLS.6 The guidelines conclude that ferric carboxymaltose (1,000 mg) is effective for treating moderate to severe RLS in those with serum ferritin less than 300 mcg/L and could be used as first-line therapy for RLS in adults, with oral iron (65 mg) possibly effective in patients with ferritin levels less than 75 mcg/L.
Pearl: Think of iron as therapy for fatigue in nonanemic women with a ferritin level less than 50 mcg/L, consider a trial of iron for thinning hair in women with ferritin levels less than 50 mcg/L, and a trial of iron in those with RLS with ferritin levels less than 75 mcg/L.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Verdon F et al. BMJ. 2003 May 24;326(7399):1124. .
2. Houston BL et al. BMJ Open. 2018 Apr 5;8(4):e019240.
3. Almohanna HM et al. Dermatol Ther (Heidelb). 2019 Mar;9(1):51-70. .
4. Hard S. Acta Derm Venereol. 1963;43:562-9.
5. Kantor J et al. J Invest Dermatol. 2003 Nov;121(5):985-8. .
6. Allen RP et al. Sleep Med. 2018 Jan;41:27-44. .
A 45-year-old women presents for evaluation of fatigue. She has been tired for the past 6 months. She has had no problems with sleep and no other new symptoms. Her physical exam is unremarkable. Her Patient Health Questionnaire–9 score is 4. Lab results are as follows: hemoglobin, 13 g/dL; hematocrit, 39%; mean corpuscular volume, 90 fL; blood urea nitrogen, 10 mg/dL; Cr, 1.0 mg/dL; AST, 20 IU/L; ALT, 15 IU/L; ferritin, 35 mcg/mL; thyroid-stimulating hormone, 3.5 mIU/L.
What would you recommend?
A. Sertraline
B. Sleep study
C. Iron supplementation
I would treat this patient with iron. Verdon and colleagues conducted a randomized, double-blind placebo-controlled trial of iron treatment in nonanemic women.1 The women who received iron had a much greater reduction in fatigue score, compared with the women who did not (P < .004). Only women with ferritin levels less than 50 mcg/L benefited. Houston and colleagues performed a systematic review of the literature of iron supplementation for fatigue and concluded that iron should be considered for treatment of fatigue in nonanemic women.2 The key number for benefit was a ferritin level less than 50 mcg/L.
Hair thinning is a common concern for many women. Does iron deficiency have a possible role in this problem? A number of studies have correlated low ferritin levels with hair loss.3 There is less clear evidence of iron treatment being effective. Hard studied 140 women with diffuse hair loss, and found 19% had iron deficiency without anemia.4 All patients with iron deficiency were treated with oral iron and in all patients hair loss ceased, and hair regrowth occurred. The target ferritin goal for treatment is greater than 40 mcg/L.5
Iron deficiency is an important trigger for restless leg syndrome (RLS). All patients who present with RLS should have ferritin checked, and appropriate evaluation for the cause of iron deficiency if ferritin levels are low. Allen and colleagues published clinical practice guidelines for iron treatment of RLS.6 The guidelines conclude that ferric carboxymaltose (1,000 mg) is effective for treating moderate to severe RLS in those with serum ferritin less than 300 mcg/L and could be used as first-line therapy for RLS in adults, with oral iron (65 mg) possibly effective in patients with ferritin levels less than 75 mcg/L.
Pearl: Think of iron as therapy for fatigue in nonanemic women with a ferritin level less than 50 mcg/L, consider a trial of iron for thinning hair in women with ferritin levels less than 50 mcg/L, and a trial of iron in those with RLS with ferritin levels less than 75 mcg/L.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Verdon F et al. BMJ. 2003 May 24;326(7399):1124. .
2. Houston BL et al. BMJ Open. 2018 Apr 5;8(4):e019240.
3. Almohanna HM et al. Dermatol Ther (Heidelb). 2019 Mar;9(1):51-70. .
4. Hard S. Acta Derm Venereol. 1963;43:562-9.
5. Kantor J et al. J Invest Dermatol. 2003 Nov;121(5):985-8. .
6. Allen RP et al. Sleep Med. 2018 Jan;41:27-44. .
A 45-year-old women presents for evaluation of fatigue. She has been tired for the past 6 months. She has had no problems with sleep and no other new symptoms. Her physical exam is unremarkable. Her Patient Health Questionnaire–9 score is 4. Lab results are as follows: hemoglobin, 13 g/dL; hematocrit, 39%; mean corpuscular volume, 90 fL; blood urea nitrogen, 10 mg/dL; Cr, 1.0 mg/dL; AST, 20 IU/L; ALT, 15 IU/L; ferritin, 35 mcg/mL; thyroid-stimulating hormone, 3.5 mIU/L.
What would you recommend?
A. Sertraline
B. Sleep study
C. Iron supplementation
I would treat this patient with iron. Verdon and colleagues conducted a randomized, double-blind placebo-controlled trial of iron treatment in nonanemic women.1 The women who received iron had a much greater reduction in fatigue score, compared with the women who did not (P < .004). Only women with ferritin levels less than 50 mcg/L benefited. Houston and colleagues performed a systematic review of the literature of iron supplementation for fatigue and concluded that iron should be considered for treatment of fatigue in nonanemic women.2 The key number for benefit was a ferritin level less than 50 mcg/L.
Hair thinning is a common concern for many women. Does iron deficiency have a possible role in this problem? A number of studies have correlated low ferritin levels with hair loss.3 There is less clear evidence of iron treatment being effective. Hard studied 140 women with diffuse hair loss, and found 19% had iron deficiency without anemia.4 All patients with iron deficiency were treated with oral iron and in all patients hair loss ceased, and hair regrowth occurred. The target ferritin goal for treatment is greater than 40 mcg/L.5
Iron deficiency is an important trigger for restless leg syndrome (RLS). All patients who present with RLS should have ferritin checked, and appropriate evaluation for the cause of iron deficiency if ferritin levels are low. Allen and colleagues published clinical practice guidelines for iron treatment of RLS.6 The guidelines conclude that ferric carboxymaltose (1,000 mg) is effective for treating moderate to severe RLS in those with serum ferritin less than 300 mcg/L and could be used as first-line therapy for RLS in adults, with oral iron (65 mg) possibly effective in patients with ferritin levels less than 75 mcg/L.
Pearl: Think of iron as therapy for fatigue in nonanemic women with a ferritin level less than 50 mcg/L, consider a trial of iron for thinning hair in women with ferritin levels less than 50 mcg/L, and a trial of iron in those with RLS with ferritin levels less than 75 mcg/L.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].
References
1. Verdon F et al. BMJ. 2003 May 24;326(7399):1124. .
2. Houston BL et al. BMJ Open. 2018 Apr 5;8(4):e019240.
3. Almohanna HM et al. Dermatol Ther (Heidelb). 2019 Mar;9(1):51-70. .
4. Hard S. Acta Derm Venereol. 1963;43:562-9.
5. Kantor J et al. J Invest Dermatol. 2003 Nov;121(5):985-8. .
6. Allen RP et al. Sleep Med. 2018 Jan;41:27-44. .
Are fish oils on the hook for AFib risk?
Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.
The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.
OMENI secondary analysis
Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.
The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.
The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.
The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.
The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
Trials of low-dose EPA and DHA
First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.
The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).
Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
Trials of very high-dose marine omega-3s
Next came trials of higher doses in higher-risk populations.
In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.
The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.
Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.
AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).
The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.
After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.
Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
Meta-analysis of marine omega-3 supplement trials
In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.
Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
Summary
When faced with surprise findings, I like to think things through.
First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).
What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.
I see multiple clinical implications of this observation.
The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.
Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.
Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.
Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.
Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.
I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.
In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.
No matter. I find the signal of increased AFib risk an important one to use at the bedside.
Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.
This allows for one of the most important interventions in AFib care: time.
Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.
The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.
OMENI secondary analysis
Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.
The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.
The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.
The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.
The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
Trials of low-dose EPA and DHA
First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.
The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).
Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
Trials of very high-dose marine omega-3s
Next came trials of higher doses in higher-risk populations.
In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.
The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.
Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.
AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).
The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.
After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.
Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
Meta-analysis of marine omega-3 supplement trials
In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.
Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
Summary
When faced with surprise findings, I like to think things through.
First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).
What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.
I see multiple clinical implications of this observation.
The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.
Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.
Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.
Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.
Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.
I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.
In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.
No matter. I find the signal of increased AFib risk an important one to use at the bedside.
Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.
This allows for one of the most important interventions in AFib care: time.
Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Questions about omega-3 fatty acid supplements come up often in the atrial fibrillation (AFib) clinic.
The story begins with the simple observation that populations who eat lots of oily fish have fewer coronary events. This correlation provoked great interest in concentrating fish oils in pill form and studying their use to promote health.
OMENI secondary analysis
Peder Myhre, MD, and colleagues recently published a secondary analysis of the OMENI trial looking at both the risk and possible causes of AFib in the omega-3 group.
The OMENI trial randomly assigned slightly more than 1,000 older patients (mean age, 75 years) post–myocardial infarction to either 1.8 g/d of fish oil supplements versus placebo for 2 years. The supplements comprised 930 mg of eicosapentaenoic acid (EPA) and 660 mg of docosahexaenoic acid (DHA). The main trial reported no difference in a composite primary endpoint of MI, revascularization, stroke, death, or hospitalization for heart failure.
The secondary analysis explored the 75% of patients in the main trial who had no history of AFib. It looked at how many in each group developed either true clinical AFib or what the authors called micro-AFib, defined as short bursts of irregular atrial activity lasting seconds.
The sub-analysis had three main findings: Patients in the supplement arm had a 90% higher rate of AFib or micro-AFib, compared with patients on placebo, EPA had the strongest effect on the association, and there was a graded risk for AFib with increasing serum EPA levels.
The authors raised the possibility that more micro-AFib might be a possible mediator of AFib risk.
Trials of low-dose EPA and DHA
First, the low-dose trials. In the ASCEND trial from 2018, more than 15,000 patients with diabetes were randomly assigned to either 1 g of omega-3 fatty acids (460-mg EPA and 380-mg DHA) or mineral oil.
The trial was neutral. After 7.4 years, the primary endpoint of MI, stroke, transient ischemic attack, or cardiovascular death occurred in 8.9% of the supplement group versus 9.2% of the placebo arm.The incidence of AFib was higher in the omega-3 group but did not reach statistical significance (2.1% vs. 1.7% for placebo; hazard ratio, 1.23; 95% confidence interval, 0.98-1.54).
Another neutral CV trial, VITAL, specifically studied the effects of marine omega-3 pills (460-mg EPA and 380-mg DHA) in older adults without heart disease, cancer, or AFib. After slightly more than 5 years, AFib occurred at a similar rate in the active arm and placebo arms (3.7% vs. 3.4% for placebo; HR, 1.09; 95% CI, 0.96-1.24; P = .19)
Trials of very high-dose marine omega-3s
Next came trials of higher doses in higher-risk populations.
In 2020, JAMA published the STRENGTH trial, which compared 4 g/d of a carboxylic acid formulation of EPA and DHA with a corn oil placebo in more than 13,000 patients who either had established atherosclerotic CV disease (ASCVD) or were at high risk for ASCVD.
The trial was terminated early because of futility and a signal of increased AFib risk in the supplement arm.
Nearly the same number of patients in the supplement versus placebo arm experienced a primary composite endpoint of major adverse cardiac events: 12.0% versus 12.2%, respectively.
AFib was a tertiary endpoint in this trial. An increase in investigator-reported new-onset AFib was observed in the omega-3 group: 2.2% vs. 1.3% for corn oil (HR, 1.69; 95% CI, 1.29-2.21; nominal P < .001).
The REDUCE-IT trial randomly assigned more than 8,000 patients who had ASCVD or diabetes and high ASCVD risk and elevated triglyceride levels to either 4 g of icosapent ethyl daily, a concentrated form of EPA, or a mineral oil placebo.
After nearly 5 years, there was a 4.8% absolute risk reduction in the primary endpoint of CV death, MI, stroke, revascularization, or unstable angina with icosapent ethyl. An increase in atherogenic biomarkers in the mineral oil placebo complicated interpretation of this trial.
Hospitalization for AFib or flutter occurred in 3.1% of the active arm versus 2.1% of the mineral oil group (P = .004).
Meta-analysis of marine omega-3 supplement trials
In 2021, Baris Gencer and colleagues performed a meta-analysis of these five trials plus 2 more (GISSI-HF and RP) looking specifically at risk for AFib. Their final analysis included more than 81,000 patients followed for nearly 5 years.
Omega 3 fatty acid supplements associated with a 25% increase in the risk for AFib (HR, 1.25; 95% CI, 1.07-1.46P =.013). Exploring further, they noted a dose-dependent relationship. Most of the increased risk occurred in trials that tested greater than 1 g/d.
Summary
When faced with surprise findings, I like to think things through.
First about plausibility. Omega-3 fatty acids clearly exert electrophysiologic effects on cardiac cells, an increase in AFib risk is plausible. The exact underlying mechanism may be unknown, but exact mechanisms are less important than actual clinical effects (see sodium-glucose cotransporter 2 inhibitors).
What about causality? Factors supporting causality include plausibility, consistency of increased AFib risk in multiple studies, and a dose-response relationship.
I see multiple clinical implications of this observation.
The first is the power of the randomized trial to inform practice. If we relied only on observational evidence, we might have assumed that since high fish consumption in populations associated with lower rates of cardiac events, fish oil supplementation would also reduce cardiac events. Other than the outlier trial, REDUCE-IT, with its mineral oil placebo, the preponderance of the randomized controlled trial evidence does not support fish oils for the reduction of CV events.
Randomized controlled trials also exposed the AFib risk. This would have been difficult to sort out in nonrandom observational studies.
Another underappreciated lesson is the notion that drugs, including supplements, can have off-target effects.
Consider the case of statin drugs. It is widely assumed that statins reduce cardiac events by lowering low-density lipoprotein cholesterol (LDL-C). Yet, statins became a mainstay not because of LDL-C lowering but because multiple trials found that this class of drugs reduced cardiac events without increasing adverse effects.
Omega-3 fatty acids reduce triglyceride levels, but this is not enough to adopt the use of these pills. The lack of consistent reduction in CV events and the off-target signal of AFib risk argue against routine use of fish-oil pills.
I will close with uncertainty. Though there is plausibility and multiple reasons to infer causality of marine omega-3s in increasing AFib risk, the effect size remains unknown.
In an editorial accompanying the recent meta-analysis, epidemiologist Michelle Samuel, MPH, PhD, and electrophysiologist Stanley Nattel, MD, cautioned readers on a technical but important point. It concerns the matter of competing risks, such as death, in the analysis of AFib risk, meaning that patients who died may have developed AFib had they lived. They provide a detailed explanation in the open access article, but the take-home is that the exact effect size is difficult to quantify without patient-level original data.
No matter. I find the signal of increased AFib risk an important one to use at the bedside.
Intermittent AFib has an unpredictable natural history. It often resolves as mysteriously as it arises. When patients take fish-oil supplements, I cite these studies, note the lack of CV protection, then I recommend stopping the pills.
This allows for one of the most important interventions in AFib care: time.
Dr. Mandrola is a clinical electrophysiologist with Baptist Medical Associates, Louisville, Ky. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
More expensive alcohol saves lives. Will it affect cancer?
This transcript has been edited for clarity.
I’d like to discuss an article that’s appeared recently in The Lancet. It looks at the impact of minimum unit pricing for alcohol on alcohol-related deaths and hospital admissions in Scotland, my home country. Why is that important to me as a cancer doctor? We know that alcohol underpins epidemiologically a whole range of different tumor types.
Anyway, it’s a really interesting experiment. It also looks at the impact of governments and health policy. In 2018, the Scottish government introduced a minimum unit pricing for alcohol of around $0.60 per unit of alcohol. The idea was that if you drive up the price of getting access to alcohol, that should reduce harm, deaths, and hospital admissions.
Wyper and colleagues did a rather nice controlled, time-interrupted series. The legislation was introduced in 2018, so they looked at our public-health databases, hospital admissions, deaths, and so on for the time span from 2012 to 2018, then for about 3 years after the introduction of legislation in 2018. They used England as a control.
What was also interesting was that the benefits were confined to the lower socioeconomic classes. One could argue, whether intended or otherwise, that this was a health-policy intervention targeted at the lower socioeconomic classes. Perhaps, one would hope as a consequence that this would reduce the health equity gap.
We know that the differences in Scotland are remarkable. When we compare the highest with the lowest socioeconomic classes, there’s a 4- to 4.5-fold difference in likelihood of death benefiting, of course, the wealthy. The health-equity gap between rich and poor is getting wider, not becoming narrower. Interventions of this sort make a difference.
Of course, there’s good evidence from other areas in which price control can make a difference. Tobacco is perhaps the best example of it. People have also talked about sugar or fat taxes to see whether their actions reduce levels of obesity, overeating, and other problems.
It’s a really nice study, with very compelling data, very well worked out in terms of the methodology and statistics. There are lives saved and lives prolonged.
What it doesn’t do is tell us about the amount of alcohol that people were taking. It shows that if you are less well off and the price of alcohol goes up, you’ve got less money to spend on alcohol. Therefore, that reduction results in the reduction in harm associated with it.
What’s really interesting is something I hadn’t realized about what’s called the alcohol-harm paradox. When you look at drinkers across the socioeconomic spectrum, including wealthy and poor drinkers, even for those who have exactly the same consumption of alcohol, there seems to be significantly more harm done to the poor than to the wealthy.
There may be some behavioral explanations for this, but they don’t explain all the difference. More work needs to be done there. It’s a really interesting story and I think a brave policy put forward by the Scottish government, which has returned rewards and is something that one would consider replicating around the world to see what other benefits might accrue from it.
I’m very interested to watch further forward over the next 2 decades to see what impact, if any, this alcohol-pricing legislation has on the incidence of cancer, looking at breast cancer, some gastrointestinal tumors, and so on, in which we know alcohol plays a part in their carcinogenesis.
Dr. Kerris a professor of cancer medicine at the University of Oxford (England). He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’d like to discuss an article that’s appeared recently in The Lancet. It looks at the impact of minimum unit pricing for alcohol on alcohol-related deaths and hospital admissions in Scotland, my home country. Why is that important to me as a cancer doctor? We know that alcohol underpins epidemiologically a whole range of different tumor types.
Anyway, it’s a really interesting experiment. It also looks at the impact of governments and health policy. In 2018, the Scottish government introduced a minimum unit pricing for alcohol of around $0.60 per unit of alcohol. The idea was that if you drive up the price of getting access to alcohol, that should reduce harm, deaths, and hospital admissions.
Wyper and colleagues did a rather nice controlled, time-interrupted series. The legislation was introduced in 2018, so they looked at our public-health databases, hospital admissions, deaths, and so on for the time span from 2012 to 2018, then for about 3 years after the introduction of legislation in 2018. They used England as a control.
What was also interesting was that the benefits were confined to the lower socioeconomic classes. One could argue, whether intended or otherwise, that this was a health-policy intervention targeted at the lower socioeconomic classes. Perhaps, one would hope as a consequence that this would reduce the health equity gap.
We know that the differences in Scotland are remarkable. When we compare the highest with the lowest socioeconomic classes, there’s a 4- to 4.5-fold difference in likelihood of death benefiting, of course, the wealthy. The health-equity gap between rich and poor is getting wider, not becoming narrower. Interventions of this sort make a difference.
Of course, there’s good evidence from other areas in which price control can make a difference. Tobacco is perhaps the best example of it. People have also talked about sugar or fat taxes to see whether their actions reduce levels of obesity, overeating, and other problems.
It’s a really nice study, with very compelling data, very well worked out in terms of the methodology and statistics. There are lives saved and lives prolonged.
What it doesn’t do is tell us about the amount of alcohol that people were taking. It shows that if you are less well off and the price of alcohol goes up, you’ve got less money to spend on alcohol. Therefore, that reduction results in the reduction in harm associated with it.
What’s really interesting is something I hadn’t realized about what’s called the alcohol-harm paradox. When you look at drinkers across the socioeconomic spectrum, including wealthy and poor drinkers, even for those who have exactly the same consumption of alcohol, there seems to be significantly more harm done to the poor than to the wealthy.
There may be some behavioral explanations for this, but they don’t explain all the difference. More work needs to be done there. It’s a really interesting story and I think a brave policy put forward by the Scottish government, which has returned rewards and is something that one would consider replicating around the world to see what other benefits might accrue from it.
I’m very interested to watch further forward over the next 2 decades to see what impact, if any, this alcohol-pricing legislation has on the incidence of cancer, looking at breast cancer, some gastrointestinal tumors, and so on, in which we know alcohol plays a part in their carcinogenesis.
Dr. Kerris a professor of cancer medicine at the University of Oxford (England). He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’d like to discuss an article that’s appeared recently in The Lancet. It looks at the impact of minimum unit pricing for alcohol on alcohol-related deaths and hospital admissions in Scotland, my home country. Why is that important to me as a cancer doctor? We know that alcohol underpins epidemiologically a whole range of different tumor types.
Anyway, it’s a really interesting experiment. It also looks at the impact of governments and health policy. In 2018, the Scottish government introduced a minimum unit pricing for alcohol of around $0.60 per unit of alcohol. The idea was that if you drive up the price of getting access to alcohol, that should reduce harm, deaths, and hospital admissions.
Wyper and colleagues did a rather nice controlled, time-interrupted series. The legislation was introduced in 2018, so they looked at our public-health databases, hospital admissions, deaths, and so on for the time span from 2012 to 2018, then for about 3 years after the introduction of legislation in 2018. They used England as a control.
What was also interesting was that the benefits were confined to the lower socioeconomic classes. One could argue, whether intended or otherwise, that this was a health-policy intervention targeted at the lower socioeconomic classes. Perhaps, one would hope as a consequence that this would reduce the health equity gap.
We know that the differences in Scotland are remarkable. When we compare the highest with the lowest socioeconomic classes, there’s a 4- to 4.5-fold difference in likelihood of death benefiting, of course, the wealthy. The health-equity gap between rich and poor is getting wider, not becoming narrower. Interventions of this sort make a difference.
Of course, there’s good evidence from other areas in which price control can make a difference. Tobacco is perhaps the best example of it. People have also talked about sugar or fat taxes to see whether their actions reduce levels of obesity, overeating, and other problems.
It’s a really nice study, with very compelling data, very well worked out in terms of the methodology and statistics. There are lives saved and lives prolonged.
What it doesn’t do is tell us about the amount of alcohol that people were taking. It shows that if you are less well off and the price of alcohol goes up, you’ve got less money to spend on alcohol. Therefore, that reduction results in the reduction in harm associated with it.
What’s really interesting is something I hadn’t realized about what’s called the alcohol-harm paradox. When you look at drinkers across the socioeconomic spectrum, including wealthy and poor drinkers, even for those who have exactly the same consumption of alcohol, there seems to be significantly more harm done to the poor than to the wealthy.
There may be some behavioral explanations for this, but they don’t explain all the difference. More work needs to be done there. It’s a really interesting story and I think a brave policy put forward by the Scottish government, which has returned rewards and is something that one would consider replicating around the world to see what other benefits might accrue from it.
I’m very interested to watch further forward over the next 2 decades to see what impact, if any, this alcohol-pricing legislation has on the incidence of cancer, looking at breast cancer, some gastrointestinal tumors, and so on, in which we know alcohol plays a part in their carcinogenesis.
Dr. Kerris a professor of cancer medicine at the University of Oxford (England). He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article first appeared on Medscape.com.
Try a little D.I.Y.
Burnout continues to be a hot topic in medicine. It seems like either you are a victim or are concerned that you may become one. Does the solution lie in a restructuring of our health care nonsystem? Or do we need to do a better job of preparing physicians for the realities of an increasingly challenging profession?
Which side of the work/life balance needs adjusting?
Obviously, it is both and a recent article in the Journal of the American Informatics Association provides some hints and suggests where we might begin to look for workable solutions. Targeting a single large university health care system, the investigators reviewed the answers provided by more than 600 attending physicians. Nearly half of the respondents reported symptoms of burnout. Those physicians feeling a higher level of EHR (electronic health record) stress were more likely to experiencing burnout. Interestingly, there was no difference in the odds of having burnout between the physicians who were receiving patient emails (MyChart messages) that had been screened by a pool support personnel and those physicians who were receiving the emails directly from the patients.
While this finding about delegating physician-patient communications may come as a surprise to some of you, it supports a series of observations I have made over the last several decades. Whether we are talking about a physicians’ office or an insurance agency, I suspect most business consultants will suggest that things will run more smoothly and efficiently if there is well-structured system in which incoming communications from the clients/patients are dealt with first by less skilled, and therefore less costly, members of the team before they are passed on to the most senior personnel. It just makes sense.
But, it doesn’t always work that well. If the screener has neglected to ask a critical question or anticipated a question by the ultimate decision-makers, this is likely to require another interaction between the client and then screener and then the screener with the decision-maker. If the decision-maker – let’s now call her a physician – had taken the call directly from the patient, it would have saved three people some time and very possibly ended up with a higher quality response, certainly a more patient-friendly one.
I can understand why you might consider my suggestion unworkable when we are talking about phone calls. It will only work if you dedicate specific call-in times for the patients as my partner and I did back in the dark ages. However, when we are talking about a communication a bit less time critical (e.g. an email or a text), it becomes very workable and I think that’s what this recent paper is hinting at.
Too many of us have adopted a protectionist attitude toward our patients in which somehow it is unprofessional or certainly inefficient to communicate with them directly unless we are sitting down together in our offices. Please, not in the checkout at the grocery store. I hope this is not because, like lawyers, we feel we can’t bill for it. The patients love hearing from you directly even if you keep your responses short and to the point. Many will learn to follow suit and adopt your communication style.
You can argue that your staff is so well trained that your communication with the patients seldom becomes a time-gobbling ping-pong match of he-said/she-said/he-said. Then good for you. You are a better delegator than I am.
If this is your first foray into Do-It-Yourself medicine and it works, I encourage you to consider giving your own injections. It’s a clear-cut statement of the importance you attach to immunizations. And ... it will keep your staffing overhead down.
Finally, I can’t resist adding that the authors of this paper also found that physicians sleeping less than 6 hours per night had a significantly higher odds of burnout.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Burnout continues to be a hot topic in medicine. It seems like either you are a victim or are concerned that you may become one. Does the solution lie in a restructuring of our health care nonsystem? Or do we need to do a better job of preparing physicians for the realities of an increasingly challenging profession?
Which side of the work/life balance needs adjusting?
Obviously, it is both and a recent article in the Journal of the American Informatics Association provides some hints and suggests where we might begin to look for workable solutions. Targeting a single large university health care system, the investigators reviewed the answers provided by more than 600 attending physicians. Nearly half of the respondents reported symptoms of burnout. Those physicians feeling a higher level of EHR (electronic health record) stress were more likely to experiencing burnout. Interestingly, there was no difference in the odds of having burnout between the physicians who were receiving patient emails (MyChart messages) that had been screened by a pool support personnel and those physicians who were receiving the emails directly from the patients.
While this finding about delegating physician-patient communications may come as a surprise to some of you, it supports a series of observations I have made over the last several decades. Whether we are talking about a physicians’ office or an insurance agency, I suspect most business consultants will suggest that things will run more smoothly and efficiently if there is well-structured system in which incoming communications from the clients/patients are dealt with first by less skilled, and therefore less costly, members of the team before they are passed on to the most senior personnel. It just makes sense.
But, it doesn’t always work that well. If the screener has neglected to ask a critical question or anticipated a question by the ultimate decision-makers, this is likely to require another interaction between the client and then screener and then the screener with the decision-maker. If the decision-maker – let’s now call her a physician – had taken the call directly from the patient, it would have saved three people some time and very possibly ended up with a higher quality response, certainly a more patient-friendly one.
I can understand why you might consider my suggestion unworkable when we are talking about phone calls. It will only work if you dedicate specific call-in times for the patients as my partner and I did back in the dark ages. However, when we are talking about a communication a bit less time critical (e.g. an email or a text), it becomes very workable and I think that’s what this recent paper is hinting at.
Too many of us have adopted a protectionist attitude toward our patients in which somehow it is unprofessional or certainly inefficient to communicate with them directly unless we are sitting down together in our offices. Please, not in the checkout at the grocery store. I hope this is not because, like lawyers, we feel we can’t bill for it. The patients love hearing from you directly even if you keep your responses short and to the point. Many will learn to follow suit and adopt your communication style.
You can argue that your staff is so well trained that your communication with the patients seldom becomes a time-gobbling ping-pong match of he-said/she-said/he-said. Then good for you. You are a better delegator than I am.
If this is your first foray into Do-It-Yourself medicine and it works, I encourage you to consider giving your own injections. It’s a clear-cut statement of the importance you attach to immunizations. And ... it will keep your staffing overhead down.
Finally, I can’t resist adding that the authors of this paper also found that physicians sleeping less than 6 hours per night had a significantly higher odds of burnout.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Burnout continues to be a hot topic in medicine. It seems like either you are a victim or are concerned that you may become one. Does the solution lie in a restructuring of our health care nonsystem? Or do we need to do a better job of preparing physicians for the realities of an increasingly challenging profession?
Which side of the work/life balance needs adjusting?
Obviously, it is both and a recent article in the Journal of the American Informatics Association provides some hints and suggests where we might begin to look for workable solutions. Targeting a single large university health care system, the investigators reviewed the answers provided by more than 600 attending physicians. Nearly half of the respondents reported symptoms of burnout. Those physicians feeling a higher level of EHR (electronic health record) stress were more likely to experiencing burnout. Interestingly, there was no difference in the odds of having burnout between the physicians who were receiving patient emails (MyChart messages) that had been screened by a pool support personnel and those physicians who were receiving the emails directly from the patients.
While this finding about delegating physician-patient communications may come as a surprise to some of you, it supports a series of observations I have made over the last several decades. Whether we are talking about a physicians’ office or an insurance agency, I suspect most business consultants will suggest that things will run more smoothly and efficiently if there is well-structured system in which incoming communications from the clients/patients are dealt with first by less skilled, and therefore less costly, members of the team before they are passed on to the most senior personnel. It just makes sense.
But, it doesn’t always work that well. If the screener has neglected to ask a critical question or anticipated a question by the ultimate decision-makers, this is likely to require another interaction between the client and then screener and then the screener with the decision-maker. If the decision-maker – let’s now call her a physician – had taken the call directly from the patient, it would have saved three people some time and very possibly ended up with a higher quality response, certainly a more patient-friendly one.
I can understand why you might consider my suggestion unworkable when we are talking about phone calls. It will only work if you dedicate specific call-in times for the patients as my partner and I did back in the dark ages. However, when we are talking about a communication a bit less time critical (e.g. an email or a text), it becomes very workable and I think that’s what this recent paper is hinting at.
Too many of us have adopted a protectionist attitude toward our patients in which somehow it is unprofessional or certainly inefficient to communicate with them directly unless we are sitting down together in our offices. Please, not in the checkout at the grocery store. I hope this is not because, like lawyers, we feel we can’t bill for it. The patients love hearing from you directly even if you keep your responses short and to the point. Many will learn to follow suit and adopt your communication style.
You can argue that your staff is so well trained that your communication with the patients seldom becomes a time-gobbling ping-pong match of he-said/she-said/he-said. Then good for you. You are a better delegator than I am.
If this is your first foray into Do-It-Yourself medicine and it works, I encourage you to consider giving your own injections. It’s a clear-cut statement of the importance you attach to immunizations. And ... it will keep your staffing overhead down.
Finally, I can’t resist adding that the authors of this paper also found that physicians sleeping less than 6 hours per night had a significantly higher odds of burnout.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Considering the true costs of clinical trials
This transcript has been edited for clarity.
We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.
There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.
We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.
How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?
Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.
Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently.
Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.
Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.
There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.
We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.
How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?
Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.
Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently.
Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.
Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
We need to think about the ways that participating in clinical trials results in increased out-of-pocket costs to our patients and how that limits the ability of marginalized groups to participate. That should be a problem for us.
There are many subtle and some egregious ways that participating in clinical trials can result in increased costs. We may ask patients to come to the clinic more frequently. That may mean costs for transportation, wear and tear on your car, and gas prices. It may also mean that if you work in a job where you don’t have time off, and if you’re not at work, you don’t get paid. That’s a major hit to your take-home pay.
We also need to take a close and more honest look at our study budgets and what we consider standard of care. Now, this becomes a slippery slope because there are clear recommendations that we would all agree, but there are also differences of practice and differences of opinion.
How often should patients with advanced disease, who clinically are doing well, have scans to evaluate their disease status and look for subtle evidence of progression? Are laboratory studies part of the follow-up in patients in the adjuvant setting? Did you really need a urinalysis in somebody who’s going to be starting chemotherapy? Do you need an EKG if you’re going to be giving them a drug that doesn’t have potential cardiac toxicity, for which QTc prolongation is not a problem?
Those are often included in our clinical trials. In some cases, they might be paid for by the trial. In other cases, they’re billed to the insurance provider, which means they’ll contribute to deductibles and copays will apply. It is very likely that they will cost your patient something out of pocket.
Now, this becomes important because many of our consent forms would specifically say that things that are only done for the study are paid for by the study. How we define standard of care becomes vitally important. These issues have not been linked in this way frequently.
Clinical trials are how we make progress. The more patients who are able to participate in clinical trials, the better it is for all of us and all our future patients.
Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. She disclosed no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.