Clinical Endocrinology News

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

Another randomized trial, on the heels of the recently published SAMSON, has concluded – many would say confirmed – that statin therapy is no more likely than placebo to “cause” muscle pain in most patients who report such symptoms while taking the drugs.

Affected patients who sorely doubt that conclusion might possibly embrace statins, researchers say, if the new trial’s creative methodology could somehow be applied to them in clinical practice.

The recent SAMSON trial made waves in November 2020 by concluding, with some caveats, that about 90% of the burden of muscle symptoms reported by patients on statins may be attributable to a nocebo effect; that is, they are attributed to the drugs – perhaps because of negative expectations – but not actually caused by them.

The new trial, StatinWISE (Statin Web-based Investigation of Side Effects), triple the size but similar in design and conducted parallel to SAMSON, similarly saw no important differences in patient-reported muscle symptom prevalence or severity during administration of atorvastatin 20 mg/day or placebo, in withdrawal from the study because of such symptoms, or in patient quality of life.

The findings also support years of observational evidence that argues against a statin effect on muscle symptoms except in rare cases of confirmed myopathy, as well as results from randomized trials like ODYSSEY ALTERNATIVE and GAUSS-3, in which significant muscle symptoms in “statin-intolerant” patients were unusual, note StatinWISE investigators in their report, published online Feb. 24 in BMJ, with lead author Emily Herrett, MSc, PhD, London School of Hygiene and Tropical Medicine.

“I’m hoping it can change minds a bit and reassure people. That was part of the reason we did it, to inform this debate about harms and benefits of statins,” principal investigator Liam Smeeth, MBChB, MSc, PhD, from the same institution, said during a virtual press conference on the trial conducted by the U.K. nonprofit Science Media Centre.

“In thinking through whether to take a statin or not, people can be reassured that these muscle symptoms are rare; they aren’t common. Aches and pains are common, but are not caused by statins,” said Dr. Smeeth, who is senior author on the trial publication.

Another goal of the 200-patient study, he said, was to explore whether patients who had experienced muscle symptoms on a statin but were willing to explore whether the statin was to blame could be convinced – depending on what they learned in the trial – to stay on the drugs.

It seemed to work; two-thirds of the participants who finished the study “decided that they would actually want to try starting statins again, which was quite amazing.”

But there was a “slight caveat,” Dr. Smeeth observed. “To join our trial, yes, you had to have had a bad experience with statins, but you probably had to be a little bit open to the idea of trying them again. So, I can’t claim that that two-thirds would apply to everybody in the population.”

Because StatinWISE entered only patients who had reported severe muscle symptoms on a statin but hadn’t showed significant enzymatic evidence of myopathy, all had either taken themselves off the statin or were “considering” it. And the study had excluded anyone with “persistent, generalized, unexplained muscle pain” regardless of any statin therapy.

“This was very deliberately a select group of people who had serious problems taking statins. This was not a random sample by any means,” Dr. Smeeth said.

“The patients in the study were willing to participate and take statins again,” suggesting they “may not be completely representative of all those who believe they experience side effects with statins, as anyone who refused to take statins ever again would not have been recruited,” observed Tim Chico, MBChB, MD, University of Sheffield (England) in a Science Media Centre press release on StatinWISE.

Still, even among this “supersaturated group of people” selected for having had muscle symptoms on statins, Dr. Smeeth said at the briefing, “in almost all cases, their pains and aches were no worse on statins than they were on placebo. We’re not saying that anyone is making up their aches and pains. These are real aches and pains. What we’re showing very clearly is that those aches and pains are no worse on statins than they are on placebo.”
 

Rechallenge is possible

Some people are more likely than others to experience adverse reactions to any drug, “and that’s true of statins,” Neil J. Stone, MD, Northwestern University, Chicago, told this news organization. But StatinWISE underscores that many patients with muscle symptoms on the drugs can be convinced to continue with them rather than stop them entirely.

“The study didn’t say that everybody who has symptoms on a statin is having a nocebo effect,” said Dr. Stone, vice chair for the multisociety 2018 Guideline on the Management of Blood Cholesterol, who was not involved with StatinWISE.

“It simply said,” allowing for some caveats, “that a significant number of patients may have symptoms that don’t preclude them from being rechallenged with a statin again, once they understand what this nocebo effect is.”

And, Dr. Stone said, “it amplifies the 2018 guidelines, with their emphasis on the clinician-patient discussion before starting therapy,” by showing that statin-associated muscle pain isn’t necessarily caused by the drugs and isn’t a reason to stop them.

“That there is a second study confirming SAMSON is helpful, and the results are helpful because they say many of these patients, once they are shown the results, can be rechallenged and will then tolerate statins,” Steven E. Nissen, MD, Cleveland Clinic, said in an interview.

“They were able to get two-thirds of those completing the trial into long-term treatment, which I think is obviously very admirable and very important,” said Dr. Nissen, who was GAUSS-3 principal investigator but not associated with StatinWISE.

“I think it is important, however, that we not completely dismiss patients who complain of adverse effects. Because, in fact, there probably are some people who do have muscle-related symptoms,” he said. “But you know, to really call somebody statin intolerant, they really should fail three statins, which would be a very good standard.”

In his experience, said Patrick M. Moriarty, MD, who directs the Atherosclerosis & Lipoprotein-Apheresis Center at the University of Kansas Medical Center, Kansas City, perhaps 80%-90% of patients who believe they are statin intolerant because of muscle symptoms are actually not statin intolerant at all.

“I think a massive amount of it is supratentorial,” Dr. Moriarty, who was not part of StatinWISE, told this news organization. It comes directly from “what they heard, what they read, or what they were told – and at their age, they’re going to have aches and pains.”
 

Value of the n-of-1 trial

Dr. Smeeth and colleagues framed StatinWISE in part as a test of a strategy for overcoming nocebo-based aversion to statins. One goal was to see whether these methods might be helpful in practice for convincing patients who want to reject statins because of muscle symptoms to give the drugs another chance.

In StatinWISE, patients were individually assigned to take atorvastatin or placebo in randomized order with multiple blinding during each of six successive 2-month periods, so that they were on one or the other agent half the time. They rated their symptoms at the end of each period.

So the trial in composite was, as the publication states, “a series of randomized, placebo-controlled n-of-1 trials.” SAMSON followed a similar scheme, except – as previously reported – it had specified 4 months of atorvastatin, 4 months of placebo, and 4 months with patients on neither statin nor placebo.

StatinWISE “provides a useful approach (the n = 1 study) that could be used in real life to help patients understand the cause of their own possible side effects, which could also be applied to medications other than statins,” Dr. Chico added in the Science Media Centre release.

“I often encounter people who have a firmly held view that statins cause muscle pains, even when they haven’t taken these medications themselves, and I hope that this study may help change this view and make them willing to try such an ‘experiment,’ ” he said.

Others aren’t sure an experiment resembling an n-of-1 trial would be practical or effective when conducted in routine practice.

More efficient and useful, Dr. Moriarty noted, would be for physicians to nurture a close relationship with patients, one that could help transform their negative feelings about statins into a willingness to accept the drugs. “This is a trust you have to build; these are human beings.”

He said getting the patient’s confidence is critical. “You have to explain the pluses and minuses of getting treatment, of the 30% reduction in cardiovascular events that occur with the statin. You don’t go ‘testing this and that.’ I think it’s more about getting them on board.”
 

No statin effect on muscle symptoms

Patients in StatinWISE were recruited from 50 primary care practices in England and Wales from December 2016 to April 2018, the report notes; their mean age was 69 years, and 58% were men. Of the 200 patients, 151 recorded muscle-symptom scores for at least one statin period and one placebo period, and so were included in the primary-endpoint assessment.

The mean muscle symptom score was lower on statin therapy than on placebo (1.68 vs. 2.57), but there was no significant difference in adjusted analysis (mean difference, –0.11 (95% confidence interval, –0.36 to 0.14; P = .40).

Statins showed no significant effect on development of muscle symptoms overall, it was reported, with an odds ratio of 1.11 (99% confidence interval, 0.62-1.99). Nor was there an effect on “muscle symptoms that could not be attributed to another cause,” (OR, 1.22; 95% CI, 0.77-1.94).

Of the 80 withdrawals during the study for any reason, 43% occurred when the patient was on the statin, 49% when the patient was on placebo, and 9% after randomization but before either statin or placebo had been initiated. Of those, 33 were because of “intolerable muscle symptoms,” says the report. But withdrawal occurred about as often on statin therapy as off the drug – 9% and 7%, respectively – throughout the 1-year study.

“This study provides further evidence through the lived experience of individuals that muscle pains often attributed to statins are not due to the drug,” said Sir Nilesh J. Samani, MBChB, MD, medical director for the British Heart Foundation, as quoted in the Science Media Centre press release.

“The use of each patient as their own control in the trial provides a powerful way of distinguishing the effect of a statin from that of taking a pill,” he said. “The findings should give confidence to patients who may be concerned about taking statins.”

StatinWISE was funded by the National Institute for Health Research-Health Technology Program and sponsored by the London School of Hygiene and Tropical Medicine. The authors declare that they have “no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.” Dr. Smeeth reports receiving grants from GlaxoSmithKline, and personal fees for advisory work from AstraZeneca and GlaxoSmithKline. Dr. Stone reports no industry relationships or other disclosures. Dr. Nissen reports that his center has received funding for clinical trials from AbbVie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Orexigen, Pfizer, Takeda, The Medicines Company, and Silence Therapeutics; that he is involved in these trials but receives no personal remuneration; and that he consults for many pharmaceutical companies but requires them to donate all honoraria or fees directly to charity so that he receives neither income nor a tax deduction. Dr. Chico had no conflicts. Dr. Moriarty declared no relevant conflicts of interest. Dr. Samani had no disclosures.

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

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

About half of 148 patients hospitalized with COVID-19 infection and elevated troponin levels had at least some evidence of myocardial injury on cardiac magnetic resonance (CMR) imaging 2 months later, a new study shows.

“Our results demonstrate that in this subset of patients surviving severe COVID-19 and with troponin elevation, ongoing localized myocardial inflammation, whilst less frequent than previously reported, remains present in a proportion of patients and may represent an emerging issue of clinical relevance,” wrote Marianna Fontana, MD, PhD, of University College London, and colleagues.

The cardiac abnormalities identified were classified as nonischemic (including “myocarditis-like” late gadolinium enhancement [LGE]) in 26% of the cohort; as related to ischemic heart disease (infarction or inducible ischemia) in 22%; and as dual pathology in 6%.

Left ventricular (LV) function was normal in 89% of the 148 patients. In the 17 patients (11%) with LV dysfunction, only four had an ejection fraction below 35%. Of the nine patients whose LV dysfunction was related to myocardial infarction, six had a known history of ischemic heart disease.

European Heart Journal

Glass half full

Taking a “glass half full” approach, co–senior author Graham D. Cole, MD, PhD, noted on Twitter that nearly half the patients had no major cardiac abnormalities on CMR just 2 months after a bout with troponin-positive COVID-19.

“We think this is important: Even in a group who had been very sick with raised troponin, it was common to find no evidence of heart damage,” said Dr. Cole, of the Royal Free London NHS Foundation Trust.

“We believe our data challenge the hypothesis that chronic inflammation, diffuse fibrosis, or long-term LV dysfunction is a dominant feature in those surviving COVID-19,” the investigators concluded in their report.

In an interview, Dr. Fontana explained further: “It has been reported in an early ‘pathfinder’ study that two-thirds of patients recovered from COVID-19 had CMR evidence of abnormal findings with a high incidence of elevated T1 and T2 in keeping with diffuse fibrosis and edema. Our findings with a larger, multicenter study and better controls show low rates of heart impairment and much less ongoing inflammation, which is reassuring.”

She also noted that the different patterns of injury suggest that different mechanisms are at play, including the possibility that “at least some of the found damage might have been preexisting, because people with heart damage are more likely to get severe disease.”

The investigators, including first author Tushar Kotecha, MBChB, PhD, of the Royal Free London NHS Foundation Trust, also noted that myocarditis-like injury was limited to three or fewer myocardial segments in 88% of cases with no associated ventricular dysfunction, and that biventricular function was no different than in those without myocarditis.

“We use the word ‘myocarditis-like’ but we don’t have histology,” Dr. Fontana said. “Our group actually suspects a lot of this will be microvascular clotting (microangiopathic thrombosis). This is exciting, as newer anticoagulation strategies – for example, those being tried in RECOVERY – may have benefit.”

Aloke V. Finn, MD, of the CVPath Institute in Gaithersburg, Md., wishes researchers would stop using the term myocarditis altogether to describe clinical or imaging findings in COVID-19.

“MRI can’t diagnose myocarditis. It is a specific diagnosis that requires, ideally, histology, as the investigators acknowledged,” Dr. Finn said in an interview.

His group at CVPath recently published data showing pathologic evidence of myocarditis after SARS-CoV-2 infection, as reported by theheart.org | Medscape Cardiology.

“As a clinician, when I think of myocarditis, I look at the echo and an LV gram, and I see if there is a wall motion abnormality and troponin elevation, but with normal coronary arteries. And if all that is there, then I think about myocarditis in my differential diagnosis,” he said. “But in most of these cases, as the authors rightly point out, most patients did not have what is necessary to really entertain a diagnosis of myocarditis.”

He agreed with Dr. Fontana’s suggestion that what the CMR might be picking up in these survivors is microthrombi, as his group saw in their recent autopsy study.

“It’s very possible these findings are concordant with the recent autopsy studies done by my group and others in terms of detecting the presence of microthrombi, but we don’t know this for certain because no one has ever studied this entity before in the clinic and we don’t really know how microthrombi might appear on CMR.”
 

Largest study to date

The 148 participants (mean age, 64 years; 70% male) in the largest study to date to investigate convalescing COVID-19 patients who had elevated troponins – something identified early in the pandemic as a risk factor for worse outcomes in COVID-19 – were treated at one of six hospitals in London.

Patients who had abnormal troponin levels were offered an MRI scan of the heart after discharge and were compared with those from a control group of patients who had not had COVID-19 and with 40 healthy volunteers.

Median length of stay was 9 days, and 32% of patients required ventilatory support in the intensive care unit.

Just over half the patients (57%) had hypertension, 7% had had a previous myocardial infarction, 34% had diabetes, 46% had hypercholesterolemia, and 24% were smokers. Mean body mass index was 28.5 kg/m².

CMR follow-up was conducted a median of 68 days after confirmation of a COVID-19 diagnosis.

On Twitter, Dr. Cole noted that the findings are subject to both survivor bias and referral bias. “We didn’t scan frail patients where the clinician felt [CMR] was unlikely to inform management.”

The findings, said Dr. Fontana, “say nothing about what happens to people who are not hospitalized with COVID, or those who are hospitalized but without elevated troponin.”

What they do offer, particularly if replicated, is a way forward in identifying patients at higher or lower risk for long-term sequelae and inform strategies that could improve outcomes, she added.

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson & Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson & Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson & Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

Roughly 40% of all U.S. cases of incident diabetes during 2013-2016 were directly attributable to obesity, a finding that further solidifies the major etiologic role for obesity in the current American diabetes epidemic.

Researchers used data from a diverse cohort of 4,200 American adults in the MESA study during 2000-2017 to calculate a relative risk for developing diabetes of 2.7 in people with obesity compared with similar participants without obesity.

They then applied this relative risk estimate to obesity prevalence rates during serial iterations of NHANES, the recurring U.S.-wide survey of vital statistics in a representative cross-sectional population.

Their calculations showed that, during 2013-2016, 41% of U.S. adults who developed new onset diabetes did so because of obesity, after the researchers adjusted for potential confounders.

This “population attributable fraction,” or disease burden attributable to obesity, varied somewhat by sex, and by racial and ethnic subgrouping. Obesity was linked with the highest attributable rate among non-Hispanic White women, a rate of 53%, and with the lowest rate among non-Hispanic Black men, with an attributable fraction of 30%, Natalie A. Cameron, MD, and colleagues reported in their study, published online Feb. 10 in the Journal of the American Heart Association.
 

Potential for “meaningful impact” by reducing obesity

“Our study highlights the meaningful impact that reducing obesity could have on type 2 diabetes prevention in the United States. Decreasing obesity needs to be a priority,” Dr. Cameron, of the McGaw Medical Center of Northwestern University in Chicago, said in a statement issued by the American Heart Association.

“Public health efforts that support healthy lifestyles, such as increasing access to nutritious foods, promoting physical activity, and developing community programs to prevent obesity, could substantially reduce new cases of type 2 diabetes,” she added.

MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults aged 45-84 years and free from clinical cardiovascular disease at six U.S. sites during 2000-2002, and then followed them with four additional examinations through 2017.

For the current study, researchers narrowed the cohort down to 4,200 participants who were aged 45-79 years and free from diabetes at entry, and also restricted this subgroup to participants classified as non-Hispanic White (54% of the cohort), non-Hispanic Black (33%), or Mexican American (13%). At entry, 34% of the cohort had obesity, with a body mass index of at least 30 kg/m².

During a median follow-up of just over 9 years, 12% of the cohort developed incident diabetes. After adjustment for possible confounders, a hazard ratio model showed an overall 2.7-fold higher rate of incident diabetes among people with obesity compared to those without.

The researchers then applied this hazard ratio to obesity prevalence statistics from NHANES (National Health and Nutrition Examination Survey) during the same time period, with data from the biennial NHANES project collapsed into four time strata: 2001-2004, 2005-2008, 2009-2012, and 2013-2016. They again limited their analysis to NHANES data collected from people aged 45-79 years who self-reported categorization as non-Hispanic White, non-Hispanic Black, or Mexican American.

During the period from 2001-2004 to 2013-2016, overall obesity prevalence tallied by NHANES data rose from 34% to 41%. Among people with type 2 diabetes during 2013-2016, obesity prevalence was 65%.

To calculate the population attributable fraction researchers combined the MESA and NHANES estimates and adjusted for potential confounders and found that, overall, in 41% of people with incident diabetes during 2013-2016, the disease was attributable to obesity.

The study received no commercial funding, and none of the authors had disclosures.

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

Roughly 40% of all U.S. cases of incident diabetes during 2013-2016 were directly attributable to obesity, a finding that further solidifies the major etiologic role for obesity in the current American diabetes epidemic.

Researchers used data from a diverse cohort of 4,200 American adults in the MESA study during 2000-2017 to calculate a relative risk for developing diabetes of 2.7 in people with obesity compared with similar participants without obesity.

They then applied this relative risk estimate to obesity prevalence rates during serial iterations of NHANES, the recurring U.S.-wide survey of vital statistics in a representative cross-sectional population.

Their calculations showed that, during 2013-2016, 41% of U.S. adults who developed new onset diabetes did so because of obesity, after the researchers adjusted for potential confounders.

This “population attributable fraction,” or disease burden attributable to obesity, varied somewhat by sex, and by racial and ethnic subgrouping. Obesity was linked with the highest attributable rate among non-Hispanic White women, a rate of 53%, and with the lowest rate among non-Hispanic Black men, with an attributable fraction of 30%, Natalie A. Cameron, MD, and colleagues reported in their study, published online Feb. 10 in the Journal of the American Heart Association.
 

Potential for “meaningful impact” by reducing obesity

“Our study highlights the meaningful impact that reducing obesity could have on type 2 diabetes prevention in the United States. Decreasing obesity needs to be a priority,” Dr. Cameron, of the McGaw Medical Center of Northwestern University in Chicago, said in a statement issued by the American Heart Association.

“Public health efforts that support healthy lifestyles, such as increasing access to nutritious foods, promoting physical activity, and developing community programs to prevent obesity, could substantially reduce new cases of type 2 diabetes,” she added.

MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults aged 45-84 years and free from clinical cardiovascular disease at six U.S. sites during 2000-2002, and then followed them with four additional examinations through 2017.

For the current study, researchers narrowed the cohort down to 4,200 participants who were aged 45-79 years and free from diabetes at entry, and also restricted this subgroup to participants classified as non-Hispanic White (54% of the cohort), non-Hispanic Black (33%), or Mexican American (13%). At entry, 34% of the cohort had obesity, with a body mass index of at least 30 kg/m².

During a median follow-up of just over 9 years, 12% of the cohort developed incident diabetes. After adjustment for possible confounders, a hazard ratio model showed an overall 2.7-fold higher rate of incident diabetes among people with obesity compared to those without.

The researchers then applied this hazard ratio to obesity prevalence statistics from NHANES (National Health and Nutrition Examination Survey) during the same time period, with data from the biennial NHANES project collapsed into four time strata: 2001-2004, 2005-2008, 2009-2012, and 2013-2016. They again limited their analysis to NHANES data collected from people aged 45-79 years who self-reported categorization as non-Hispanic White, non-Hispanic Black, or Mexican American.

During the period from 2001-2004 to 2013-2016, overall obesity prevalence tallied by NHANES data rose from 34% to 41%. Among people with type 2 diabetes during 2013-2016, obesity prevalence was 65%.

To calculate the population attributable fraction researchers combined the MESA and NHANES estimates and adjusted for potential confounders and found that, overall, in 41% of people with incident diabetes during 2013-2016, the disease was attributable to obesity.

The study received no commercial funding, and none of the authors had disclosures.

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

Roughly 40% of all U.S. cases of incident diabetes during 2013-2016 were directly attributable to obesity, a finding that further solidifies the major etiologic role for obesity in the current American diabetes epidemic.

Researchers used data from a diverse cohort of 4,200 American adults in the MESA study during 2000-2017 to calculate a relative risk for developing diabetes of 2.7 in people with obesity compared with similar participants without obesity.

They then applied this relative risk estimate to obesity prevalence rates during serial iterations of NHANES, the recurring U.S.-wide survey of vital statistics in a representative cross-sectional population.

Their calculations showed that, during 2013-2016, 41% of U.S. adults who developed new onset diabetes did so because of obesity, after the researchers adjusted for potential confounders.

This “population attributable fraction,” or disease burden attributable to obesity, varied somewhat by sex, and by racial and ethnic subgrouping. Obesity was linked with the highest attributable rate among non-Hispanic White women, a rate of 53%, and with the lowest rate among non-Hispanic Black men, with an attributable fraction of 30%, Natalie A. Cameron, MD, and colleagues reported in their study, published online Feb. 10 in the Journal of the American Heart Association.
 

Potential for “meaningful impact” by reducing obesity

“Our study highlights the meaningful impact that reducing obesity could have on type 2 diabetes prevention in the United States. Decreasing obesity needs to be a priority,” Dr. Cameron, of the McGaw Medical Center of Northwestern University in Chicago, said in a statement issued by the American Heart Association.

“Public health efforts that support healthy lifestyles, such as increasing access to nutritious foods, promoting physical activity, and developing community programs to prevent obesity, could substantially reduce new cases of type 2 diabetes,” she added.

MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults aged 45-84 years and free from clinical cardiovascular disease at six U.S. sites during 2000-2002, and then followed them with four additional examinations through 2017.

For the current study, researchers narrowed the cohort down to 4,200 participants who were aged 45-79 years and free from diabetes at entry, and also restricted this subgroup to participants classified as non-Hispanic White (54% of the cohort), non-Hispanic Black (33%), or Mexican American (13%). At entry, 34% of the cohort had obesity, with a body mass index of at least 30 kg/m².

During a median follow-up of just over 9 years, 12% of the cohort developed incident diabetes. After adjustment for possible confounders, a hazard ratio model showed an overall 2.7-fold higher rate of incident diabetes among people with obesity compared to those without.

The researchers then applied this hazard ratio to obesity prevalence statistics from NHANES (National Health and Nutrition Examination Survey) during the same time period, with data from the biennial NHANES project collapsed into four time strata: 2001-2004, 2005-2008, 2009-2012, and 2013-2016. They again limited their analysis to NHANES data collected from people aged 45-79 years who self-reported categorization as non-Hispanic White, non-Hispanic Black, or Mexican American.

During the period from 2001-2004 to 2013-2016, overall obesity prevalence tallied by NHANES data rose from 34% to 41%. Among people with type 2 diabetes during 2013-2016, obesity prevalence was 65%.

To calculate the population attributable fraction researchers combined the MESA and NHANES estimates and adjusted for potential confounders and found that, overall, in 41% of people with incident diabetes during 2013-2016, the disease was attributable to obesity.

The study received no commercial funding, and none of the authors had disclosures.

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

The Food and Drug Administration on Feb. 22 updated its October 2020 guidance for manufacturers developing COVID-19 vaccines, diagnostics, and treatments in the wake of circulating SARS-CoV-2 variants.

The United States is currently facing three main variant threats, according to the Centers for Disease Control and Prevention: B.1.1.7, which originated in the United Kingdom; B.1.351 from South Africa; and the P.1 variant, which originated in Brazil.

Acting FDA Commissioner Janet Woodcock, MD, said on a telephone press briefing call Feb. 22 that the FDA has already been communicating with individual manufacturers as they assess the variants’ effect on their products, but these guidelines are issued for the sake of transparency and to welcome scientific input.
 

Tailoring may be necessary

Dr. Woodcock emphasized that, “at this time, available data suggest the FDA-authorized vaccines are effective in protecting circulating strains of SARS-CoV-2.” However, in the event the strains start to show resistance, it may be necessary to tailor the vaccine to the variant.

In that case, effectiveness of a modified vaccine should be determined by data from clinical immunogenicity studies, which would compare a recipient’s immune response with virus variants induced by the modified vaccine against the immune response to the authorized vaccine, the guidance states.

Manufacturers should also study the vaccine in both nonvaccinated people and people fully vaccinated with the authorized vaccine, according to the guidance.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said on the call that the clinical immunogenicity data is needed to understand, for instance, whether a new vaccine strain is able to cover the new and old strain or whether it just covers the new strain. Information is also needed to understand whether the modified vaccine, when given to someone fully vaccinated, will still promote a positive response without introducing safety concerns.

Further discussions will be necessary to decide whether future modified vaccines may be authorized without the need for clinical studies.
 

Variants and testing

The FDA’s updated guidance for test developers, Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests, includes information that test performance can be influenced by the sequence of the variant, prevalence of the variant in the population, or design of the test. For example, molecular tests designed to detect multiple SARS-CoV-2 genetic targets are less susceptible to genetic variants than tests designed to detect a single genetic target.

The FDA already issued a safety alert on Jan. 8 to caution that genetic mutations to the virus in a patient sample can potentially change the performance of a diagnostic test. The FDA identified three tests that had been granted emergency-use authorization (EUA) that are known to be affected.

However, Dr. Woodcock said on the call, “at this time the impact does not appear to be significant.”
 

Updated guidance for therapeutics

The FDA has issued new guidance on the effect of variants on monoclonal antibody treatments.

“The FDA is aware that some of the monoclonal antibodies that have been authorized are less active against some of the SARS-CoV-2 variants that have emerged,” the FDA noted in its press release. “This guidance provides recommendations on efficient approaches to the generation of ... manufacturing and controls data that could potentially support an EUA for monoclonal antibody products that may be effective against emerging variants.”

While the FDA is monitoring the effects of variants, manufacturers bear a lot of the responsibility as well.

The FDA added: “With these guidances, the FDA is encouraging developers of drugs or biological products targeting SARS-CoV-2 to continuously monitor genomic databases for emerging SARS-CoV-2 variants and evaluate phenotypically any specific variants in the product target that are becoming prevalent or could potentially impact its activity.”

Dr.Woodcock added that “we urge all Americans to continue to get tested, get their vaccines when available, and follow important heath measures such as handwashing, masking, and social distancing.”

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

The Food and Drug Administration on Feb. 22 updated its October 2020 guidance for manufacturers developing COVID-19 vaccines, diagnostics, and treatments in the wake of circulating SARS-CoV-2 variants.

The United States is currently facing three main variant threats, according to the Centers for Disease Control and Prevention: B.1.1.7, which originated in the United Kingdom; B.1.351 from South Africa; and the P.1 variant, which originated in Brazil.

Acting FDA Commissioner Janet Woodcock, MD, said on a telephone press briefing call Feb. 22 that the FDA has already been communicating with individual manufacturers as they assess the variants’ effect on their products, but these guidelines are issued for the sake of transparency and to welcome scientific input.
 

Tailoring may be necessary

Dr. Woodcock emphasized that, “at this time, available data suggest the FDA-authorized vaccines are effective in protecting circulating strains of SARS-CoV-2.” However, in the event the strains start to show resistance, it may be necessary to tailor the vaccine to the variant.

In that case, effectiveness of a modified vaccine should be determined by data from clinical immunogenicity studies, which would compare a recipient’s immune response with virus variants induced by the modified vaccine against the immune response to the authorized vaccine, the guidance states.

Manufacturers should also study the vaccine in both nonvaccinated people and people fully vaccinated with the authorized vaccine, according to the guidance.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said on the call that the clinical immunogenicity data is needed to understand, for instance, whether a new vaccine strain is able to cover the new and old strain or whether it just covers the new strain. Information is also needed to understand whether the modified vaccine, when given to someone fully vaccinated, will still promote a positive response without introducing safety concerns.

Further discussions will be necessary to decide whether future modified vaccines may be authorized without the need for clinical studies.
 

Variants and testing

The FDA’s updated guidance for test developers, Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests, includes information that test performance can be influenced by the sequence of the variant, prevalence of the variant in the population, or design of the test. For example, molecular tests designed to detect multiple SARS-CoV-2 genetic targets are less susceptible to genetic variants than tests designed to detect a single genetic target.

The FDA already issued a safety alert on Jan. 8 to caution that genetic mutations to the virus in a patient sample can potentially change the performance of a diagnostic test. The FDA identified three tests that had been granted emergency-use authorization (EUA) that are known to be affected.

However, Dr. Woodcock said on the call, “at this time the impact does not appear to be significant.”
 

Updated guidance for therapeutics

The FDA has issued new guidance on the effect of variants on monoclonal antibody treatments.

“The FDA is aware that some of the monoclonal antibodies that have been authorized are less active against some of the SARS-CoV-2 variants that have emerged,” the FDA noted in its press release. “This guidance provides recommendations on efficient approaches to the generation of ... manufacturing and controls data that could potentially support an EUA for monoclonal antibody products that may be effective against emerging variants.”

While the FDA is monitoring the effects of variants, manufacturers bear a lot of the responsibility as well.

The FDA added: “With these guidances, the FDA is encouraging developers of drugs or biological products targeting SARS-CoV-2 to continuously monitor genomic databases for emerging SARS-CoV-2 variants and evaluate phenotypically any specific variants in the product target that are becoming prevalent or could potentially impact its activity.”

Dr.Woodcock added that “we urge all Americans to continue to get tested, get their vaccines when available, and follow important heath measures such as handwashing, masking, and social distancing.”

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

The Food and Drug Administration on Feb. 22 updated its October 2020 guidance for manufacturers developing COVID-19 vaccines, diagnostics, and treatments in the wake of circulating SARS-CoV-2 variants.

The United States is currently facing three main variant threats, according to the Centers for Disease Control and Prevention: B.1.1.7, which originated in the United Kingdom; B.1.351 from South Africa; and the P.1 variant, which originated in Brazil.

Acting FDA Commissioner Janet Woodcock, MD, said on a telephone press briefing call Feb. 22 that the FDA has already been communicating with individual manufacturers as they assess the variants’ effect on their products, but these guidelines are issued for the sake of transparency and to welcome scientific input.
 

Tailoring may be necessary

Dr. Woodcock emphasized that, “at this time, available data suggest the FDA-authorized vaccines are effective in protecting circulating strains of SARS-CoV-2.” However, in the event the strains start to show resistance, it may be necessary to tailor the vaccine to the variant.

In that case, effectiveness of a modified vaccine should be determined by data from clinical immunogenicity studies, which would compare a recipient’s immune response with virus variants induced by the modified vaccine against the immune response to the authorized vaccine, the guidance states.

Manufacturers should also study the vaccine in both nonvaccinated people and people fully vaccinated with the authorized vaccine, according to the guidance.

Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said on the call that the clinical immunogenicity data is needed to understand, for instance, whether a new vaccine strain is able to cover the new and old strain or whether it just covers the new strain. Information is also needed to understand whether the modified vaccine, when given to someone fully vaccinated, will still promote a positive response without introducing safety concerns.

Further discussions will be necessary to decide whether future modified vaccines may be authorized without the need for clinical studies.
 

Variants and testing

The FDA’s updated guidance for test developers, Policy for Evaluating Impact of Viral Mutations on COVID-19 Tests, includes information that test performance can be influenced by the sequence of the variant, prevalence of the variant in the population, or design of the test. For example, molecular tests designed to detect multiple SARS-CoV-2 genetic targets are less susceptible to genetic variants than tests designed to detect a single genetic target.

The FDA already issued a safety alert on Jan. 8 to caution that genetic mutations to the virus in a patient sample can potentially change the performance of a diagnostic test. The FDA identified three tests that had been granted emergency-use authorization (EUA) that are known to be affected.

However, Dr. Woodcock said on the call, “at this time the impact does not appear to be significant.”
 

Updated guidance for therapeutics

The FDA has issued new guidance on the effect of variants on monoclonal antibody treatments.

“The FDA is aware that some of the monoclonal antibodies that have been authorized are less active against some of the SARS-CoV-2 variants that have emerged,” the FDA noted in its press release. “This guidance provides recommendations on efficient approaches to the generation of ... manufacturing and controls data that could potentially support an EUA for monoclonal antibody products that may be effective against emerging variants.”

While the FDA is monitoring the effects of variants, manufacturers bear a lot of the responsibility as well.

The FDA added: “With these guidances, the FDA is encouraging developers of drugs or biological products targeting SARS-CoV-2 to continuously monitor genomic databases for emerging SARS-CoV-2 variants and evaluate phenotypically any specific variants in the product target that are becoming prevalent or could potentially impact its activity.”

Dr.Woodcock added that “we urge all Americans to continue to get tested, get their vaccines when available, and follow important heath measures such as handwashing, masking, and social distancing.”

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

Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.

Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.

When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.

“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.

“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
 

First large study of testosterone in trans men with 20-year follow-up

Transgender men often undergo testosterone therapy as part of gender-affirming treatment. 

Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.

This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.

Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.

Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.

Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).

In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.

Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.

In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
 

Current advice for trans men based on old guidance for hypogonadism

The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.

But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.

Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.

“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
 

Duration of testosterone therapy impacts risk of erythrocytosis

In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.

Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:

• Consider switching patients who use injectable testosterone to transdermal products.
• Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
• Advise patients to stop smoking.
• Pursue treatment optimization for chronic lung disease or sleep apnea.

The study had no external funding. The authors reported no relevant financial relationships.

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

Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.

Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.

When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.

“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.

“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
 

First large study of testosterone in trans men with 20-year follow-up

Transgender men often undergo testosterone therapy as part of gender-affirming treatment. 

Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.

This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.

Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.

Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.

Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).

In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.

Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.

In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
 

Current advice for trans men based on old guidance for hypogonadism

The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.

But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.

Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.

“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
 

Duration of testosterone therapy impacts risk of erythrocytosis

In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.

Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:

• Consider switching patients who use injectable testosterone to transdermal products.
• Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
• Advise patients to stop smoking.
• Pursue treatment optimization for chronic lung disease or sleep apnea.

The study had no external funding. The authors reported no relevant financial relationships.

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

Over 10% of transgender men (females transitioning to male) who take testosterone develop high hematocrit levels that could put them at greater risk for a thrombotic event, and the largest increase in levels occurs in the first year after starting therapy, a new Dutch study indicates.

Erythrocytosis, defined as a hematocrit greater than 0.50 L/L, is a potentially serious side effect of testosterone therapy, say Milou Cecilia Madsen, MD, and colleagues in their article published online Feb. 18, 2021, in the Journal of Clinical Endocrinology & Metabolism.

When hematocrit was measured twice, 11.1% of the cohort of 1073 trans men had levels in excess of 0.50 L/L over a 20-year follow-up.

“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have [a] high BMI [body mass index], and [who] use testosterone injections,” Dr. Madsen, of the VU University Medical Center Amsterdam, said in a statement from the Endocrine Society.

“A reasonable first step in the care of transgender men with high red blood cells while on testosterone is to advise them to quit smoking, switch injectable testosterone to gel, and, if BMI is high, to lose weight,” she added.
 

First large study of testosterone in trans men with 20-year follow-up

Transgender men often undergo testosterone therapy as part of gender-affirming treatment. 

Secondary erythrocytosis, a condition where the body makes too many red blood cells, is a common side effect of testosterone therapy that can increase the risk of thrombolic events, heart attack, and stroke, Dr. Madsen and colleagues explained.

This is the first study of a large cohort of trans men taking testosterone therapy followed for up to 20 years. Because of the large sample size, statistical analysis with many determinants could be performed. And because of the long follow-up, a clear time relation between initiation of testosterone therapy and hematocrit could be studied, they noted.

Participants were part of the Amsterdam Cohort of Gender Dysphoria study, a large cohort of individuals seen at the Center of Expertise on Gender Dysphoria at Amsterdam University Medical Center between 1972 and 2015.

Laboratory measurements taken between 2004 and 2018 were available for analysis. Trans men visited the center every 3-6 months during their first year of testosterone therapy and were then monitored every year or every other year.

Long-acting undecanoate injection was associated with the highest risk of a hematocrit level greater than 0.50 L/L, and the risk of erythrocytosis in those who took long-acting intramuscular injections was about threefold higher, compared with testosterone gel (adjusted odds ratio, 3.1).

In contrast, short-acting ester injections and oral administration of testosterone had a similar risk for erythrocytosis, as did testosterone gel.

Other determinants of elevated hematocrit included smoking, medical history of a number of comorbid conditions, and older age on initiation of testosterone.

In contrast, “higher testosterone levels per se were not associated with an increased odds of hematocrit greater than 0.50 L/L”, the authors noted.
 

Current advice for trans men based on old guidance for hypogonadism

The authors said that current advice for trans men is based on recommendations for testosterone-treated hypogonadal cis men (those assigned male at birth) from 2008, which advises a hematocrit greater than 0.50 L/L has a moderate to high risk of adverse outcome. For levels greater than 0.54 L/L, cessation of testosterone therapy, a dose reduction, or therapeutic phlebotomy to reduce the risk of adverse events is advised. For levels 0.50-0.54 L/L, no clear advice is given.

But questions remain as to whether these guidelines are applicable to trans men because the duration of testosterone therapy is much longer in trans men and hormone treatment often cannot be discontinued without causing distress.

Meanwhile, hematology guidelines indicate an upper limit for hematocrit for cis females of 0.48 L/L.

“It could be argued that the upper limit for cis females should be applied, as trans men are born with female genetics,” the authors said. “This is a subject for further research.”
 

Duration of testosterone therapy impacts risk of erythrocytosis

In the study, the researchers found that longer duration of testosterone therapy increased the risk of developing hematocrit levels greater than 0.50 L/L. For example, after 1 year, the cumulative incidence of erythrocytosis was 8%; after 10 years, it was 38%; and after 14 years, it was 50%.

Until more specific guidance is developed for trans men, if hematocrit levels rise to 0.50-0.54 L/L, the researchers suggested taking “reasonable” steps to prevent a further increase:

• Consider switching patients who use injectable testosterone to transdermal products.
• Advise patients with a BMI greater than 25 kg/m2 to lose weight to attain a BMI of 18.5-25.
• Advise patients to stop smoking.
• Pursue treatment optimization for chronic lung disease or sleep apnea.

The study had no external funding. The authors reported no relevant financial relationships.

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

Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.

Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.

Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.

These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.

The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.

But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
 

Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes

“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”

In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.

“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”

DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.

mzoler@mdedge.com

Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.

Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.

Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.

These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.

The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.

But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
 

Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes

“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”

In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.

“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”

DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.

mzoler@mdedge.com

Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.

Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.

Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.

These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.

The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.

But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
 

Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes

“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”

In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.

“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”

DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.

mzoler@mdedge.com

Goldenseal, a natural botanical product, may interfere with intestinal absorption of metformin, potentially compromising blood glucose control in patients with type 2 diabetes, according to investigators.

The study, which tested for interactions between goldenseal and several drugs in healthy volunteers, reveals that current models for predicting transporter-mediated drug-drug interactions may be insufficient to screen commonly used dietary supplements, reported lead investigator James T. Nguyen, PharmD, a PhD candidate at Washington State University, Spokane, and colleagues.

“Supplements containing goldenseal ... a perennial herb native to North America, have consistently ranked among the top 20 highest selling natural products during the last decade,” the investigators wrote in Clinical Pharmacology & Therapeutics . “As more patients continue to seek goldenseal and other natural products to self-treat their medical conditions, there is an increasing need to characterize their safety profiles, especially when co-consumed with prescribed medications, which can lead to adverse natural product-drug interactions.”

Previous clinical studies have shown that goldenseal inhibits cytochrome P450, with one study showing a roughly 40% increase in systemic midazolam exposure via CYP3A inhibition, “suggesting goldenseal could have prolonged inhibitory effects in vivo similar to grapefruit juice,” the investigators wrote.

Clinical and in vitro results for goldenseal-transporter interactions have been mixed, the investigators noted, specifically for P-glycoprotein, while other transporters remain clinically untested.

“Likewise, the effects of [goldenseal alkaloids], all of which are time-dependent inhibitors of CYP3A and/or CYP2D6, have not been tested on transporter function,” the investigators wrote.

To address this knowledge gap, the investigators first performed in vitro transporter inhibition assays and in vitro–in vivo predictions involving goldenseal, plus the alkaloids berberine, (−)-beta-hydrastine, and hydrastinine.

This analysis revealed that a number of transporters were sensitive to inhibition by goldenseal and its alkaloids.

“Using current [Food and Drug Administration]–recommended basic models, the goldenseal product was predicted to inhibit the intestinal efflux transporter BCRP [breast cancer resistance protein] and the hepatic uptake transporters OATP1B1 and OATP1B3,” the investigators wrote, which suggested that goldenseal would increase the area under the plasma concentration-time curve (AUC) of rosuvastatin acid and lactone.

This prediction was clinically tested in 16 healthy volunteers: 8 men and 8 nonpregnant women.

In the baseline portion of the study, each participant received an oral transporter probe cocktail consisting of 10 mg rosuvastatin (OATP1B1/3 and BCRP), 50 mg metformin (OCT1/2 and MATE1/2-K), 1 mg furosemide (OAT1/3), and 2.5 mg midazolam (CYP3A; positive control). Plasma and urine samples were collected before and after the cocktail, with urine collected up to 24 hours later, and plasma collected up to 96 hours later.

Following a minimum 9-day washout period, the same cohort received 1 gram of goldenseal every 8 hours for 5 days. On the day 6, the drug cocktail was given again, followed by two additional doses of goldenseal at 4-hour intervals. At the same time points used in the baseline protocol, urine and plasma samples were collected.

Plasma concentration vs. time profiles revealed that the model-based prediction was false, in that the presence of goldenseal did not alter the pharmacokinetics of rosuvastatin acid and lactone. The investigators suggested that this could be due to incomplete dissolution of goldenseal in the intestinal lumen, and/or low enterocyte concentrations of goldenseal stemming from “low permeability or extensive enterocyte metabolism or efflux.”

In contrast, and unpredicted by the basic model, goldenseal had a significant impact on apical efflux transporters MATE1 and MATE2-K, which mediate renal excretion of metformin. In consequence, AUC from zero to infinity and maximum plasma concentration of metformin were reduced by 23% and 27%, respectively.

“These observations, coupled with no change in half-life, suggested that goldenseal decreased metformin oral bioavailability by altering intestinal permeability, transport, and/or other processes involved in metformin absorption,” the investigators wrote.

According to principal author Mary Paine, PhD, of Washington State University, Spokane, this finding may have clinically significant implications for patients currently taking metformin for type 2 diabetes.

Goldenseal, a natural botanical product, may interfere with intestinal absorption of metformin, potentially compromising blood glucose control in patients with type 2 diabetes, according to investigators.

The study, which tested for interactions between goldenseal and several drugs in healthy volunteers, reveals that current models for predicting transporter-mediated drug-drug interactions may be insufficient to screen commonly used dietary supplements, reported lead investigator James T. Nguyen, PharmD, a PhD candidate at Washington State University, Spokane, and colleagues.

“Supplements containing goldenseal ... a perennial herb native to North America, have consistently ranked among the top 20 highest selling natural products during the last decade,” the investigators wrote in Clinical Pharmacology & Therapeutics . “As more patients continue to seek goldenseal and other natural products to self-treat their medical conditions, there is an increasing need to characterize their safety profiles, especially when co-consumed with prescribed medications, which can lead to adverse natural product-drug interactions.”

Previous clinical studies have shown that goldenseal inhibits cytochrome P450, with one study showing a roughly 40% increase in systemic midazolam exposure via CYP3A inhibition, “suggesting goldenseal could have prolonged inhibitory effects in vivo similar to grapefruit juice,” the investigators wrote.

Clinical and in vitro results for goldenseal-transporter interactions have been mixed, the investigators noted, specifically for P-glycoprotein, while other transporters remain clinically untested.

“Likewise, the effects of [goldenseal alkaloids], all of which are time-dependent inhibitors of CYP3A and/or CYP2D6, have not been tested on transporter function,” the investigators wrote.

To address this knowledge gap, the investigators first performed in vitro transporter inhibition assays and in vitro–in vivo predictions involving goldenseal, plus the alkaloids berberine, (−)-beta-hydrastine, and hydrastinine.

This analysis revealed that a number of transporters were sensitive to inhibition by goldenseal and its alkaloids.

“Using current [Food and Drug Administration]–recommended basic models, the goldenseal product was predicted to inhibit the intestinal efflux transporter BCRP [breast cancer resistance protein] and the hepatic uptake transporters OATP1B1 and OATP1B3,” the investigators wrote, which suggested that goldenseal would increase the area under the plasma concentration-time curve (AUC) of rosuvastatin acid and lactone.

This prediction was clinically tested in 16 healthy volunteers: 8 men and 8 nonpregnant women.

In the baseline portion of the study, each participant received an oral transporter probe cocktail consisting of 10 mg rosuvastatin (OATP1B1/3 and BCRP), 50 mg metformin (OCT1/2 and MATE1/2-K), 1 mg furosemide (OAT1/3), and 2.5 mg midazolam (CYP3A; positive control). Plasma and urine samples were collected before and after the cocktail, with urine collected up to 24 hours later, and plasma collected up to 96 hours later.

Following a minimum 9-day washout period, the same cohort received 1 gram of goldenseal every 8 hours for 5 days. On the day 6, the drug cocktail was given again, followed by two additional doses of goldenseal at 4-hour intervals. At the same time points used in the baseline protocol, urine and plasma samples were collected.

Plasma concentration vs. time profiles revealed that the model-based prediction was false, in that the presence of goldenseal did not alter the pharmacokinetics of rosuvastatin acid and lactone. The investigators suggested that this could be due to incomplete dissolution of goldenseal in the intestinal lumen, and/or low enterocyte concentrations of goldenseal stemming from “low permeability or extensive enterocyte metabolism or efflux.”

In contrast, and unpredicted by the basic model, goldenseal had a significant impact on apical efflux transporters MATE1 and MATE2-K, which mediate renal excretion of metformin. In consequence, AUC from zero to infinity and maximum plasma concentration of metformin were reduced by 23% and 27%, respectively.

“These observations, coupled with no change in half-life, suggested that goldenseal decreased metformin oral bioavailability by altering intestinal permeability, transport, and/or other processes involved in metformin absorption,” the investigators wrote.

According to principal author Mary Paine, PhD, of Washington State University, Spokane, this finding may have clinically significant implications for patients currently taking metformin for type 2 diabetes.

Goldenseal, a natural botanical product, may interfere with intestinal absorption of metformin, potentially compromising blood glucose control in patients with type 2 diabetes, according to investigators.

The study, which tested for interactions between goldenseal and several drugs in healthy volunteers, reveals that current models for predicting transporter-mediated drug-drug interactions may be insufficient to screen commonly used dietary supplements, reported lead investigator James T. Nguyen, PharmD, a PhD candidate at Washington State University, Spokane, and colleagues.

“Supplements containing goldenseal ... a perennial herb native to North America, have consistently ranked among the top 20 highest selling natural products during the last decade,” the investigators wrote in Clinical Pharmacology & Therapeutics . “As more patients continue to seek goldenseal and other natural products to self-treat their medical conditions, there is an increasing need to characterize their safety profiles, especially when co-consumed with prescribed medications, which can lead to adverse natural product-drug interactions.”

Previous clinical studies have shown that goldenseal inhibits cytochrome P450, with one study showing a roughly 40% increase in systemic midazolam exposure via CYP3A inhibition, “suggesting goldenseal could have prolonged inhibitory effects in vivo similar to grapefruit juice,” the investigators wrote.

Clinical and in vitro results for goldenseal-transporter interactions have been mixed, the investigators noted, specifically for P-glycoprotein, while other transporters remain clinically untested.

“Likewise, the effects of [goldenseal alkaloids], all of which are time-dependent inhibitors of CYP3A and/or CYP2D6, have not been tested on transporter function,” the investigators wrote.

To address this knowledge gap, the investigators first performed in vitro transporter inhibition assays and in vitro–in vivo predictions involving goldenseal, plus the alkaloids berberine, (−)-beta-hydrastine, and hydrastinine.

This analysis revealed that a number of transporters were sensitive to inhibition by goldenseal and its alkaloids.

“Using current [Food and Drug Administration]–recommended basic models, the goldenseal product was predicted to inhibit the intestinal efflux transporter BCRP [breast cancer resistance protein] and the hepatic uptake transporters OATP1B1 and OATP1B3,” the investigators wrote, which suggested that goldenseal would increase the area under the plasma concentration-time curve (AUC) of rosuvastatin acid and lactone.

This prediction was clinically tested in 16 healthy volunteers: 8 men and 8 nonpregnant women.

In the baseline portion of the study, each participant received an oral transporter probe cocktail consisting of 10 mg rosuvastatin (OATP1B1/3 and BCRP), 50 mg metformin (OCT1/2 and MATE1/2-K), 1 mg furosemide (OAT1/3), and 2.5 mg midazolam (CYP3A; positive control). Plasma and urine samples were collected before and after the cocktail, with urine collected up to 24 hours later, and plasma collected up to 96 hours later.

Following a minimum 9-day washout period, the same cohort received 1 gram of goldenseal every 8 hours for 5 days. On the day 6, the drug cocktail was given again, followed by two additional doses of goldenseal at 4-hour intervals. At the same time points used in the baseline protocol, urine and plasma samples were collected.

Plasma concentration vs. time profiles revealed that the model-based prediction was false, in that the presence of goldenseal did not alter the pharmacokinetics of rosuvastatin acid and lactone. The investigators suggested that this could be due to incomplete dissolution of goldenseal in the intestinal lumen, and/or low enterocyte concentrations of goldenseal stemming from “low permeability or extensive enterocyte metabolism or efflux.”

In contrast, and unpredicted by the basic model, goldenseal had a significant impact on apical efflux transporters MATE1 and MATE2-K, which mediate renal excretion of metformin. In consequence, AUC from zero to infinity and maximum plasma concentration of metformin were reduced by 23% and 27%, respectively.

“These observations, coupled with no change in half-life, suggested that goldenseal decreased metformin oral bioavailability by altering intestinal permeability, transport, and/or other processes involved in metformin absorption,” the investigators wrote.

According to principal author Mary Paine, PhD, of Washington State University, Spokane, this finding may have clinically significant implications for patients currently taking metformin for type 2 diabetes.

Work load, not personal vulnerability, may be at the root of the current physician burnout crisis, a recent study has concluded.

The cutting-edge research utilized cognitive theory and work load analysis to get at the source of burnout among practitioners. The findings indicate that, although some institutions continue to emphasize personal responsibility of physicians to address the issue, it may be the amount and structure of the work itself that triggers burnout in doctors.

“We evaluated the cognitive load of a clinical workday in a national sample of U.S. physicians and its relationship with burnout and professional satisfaction,” wrote Elizabeth Harry, MD, SFHM, a hospitalist at the University of Colorado at Denver, Aurora and coauthors. The results were reported in the Joint Commission Journal on Quality and Patient Safety.

The researchers investigated whether task load correlated with burnout scores in a large national study of U.S. physicians from October 2017 to March 2018.

As the delivery of health care becomes more complex, physicians are charged with ever-increasing amount of administrative and cognitive tasks. Recent evidence indicates that this growing complexity of work is tied to a greater risk of burnout in physicians, compared with workers in other fields. Cognitive load theory, pioneered by psychologist Jonathan Sweller, identified limitations in working memory that humans depend on to carry out cognitive tasks. Cognitive load refers to the amount of working memory used, which can be reduced in the presence of external emotional or physiological stressors. While a potential link between cognitive load and burnout may seem self-evident, the correlation between the cognitive load of physicians and burnout has not been evaluated in a large-scale study until recently.

wutwhanfoto/Getty Images

Physician task load (PTL) was measured using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), a validated questionnaire frequently used to evaluate the cognitive load of work environments, including health care environments. Four domains (perception of effort and mental, physical, and temporal demands) were used to calculate the total PTL score.

Burnout was evaluated using the Emotional Exhaustion and Depersonalization scales of the Maslach Burnout Inventory, a validated tool considered the gold standard for measurement.

The survey sample consisted of physicians of all specialties and was assembled using the American Medical Association Physician Masterfile, an almost complete record of all U.S. physicians independent of AMA membership. All responses were anonymous and participation was voluntary.
 

Results

Among 30,456 physicians who received the survey, 5,197 (17.1%) responded. In total, 5,276 physicians were included in the analysis.

The median age of respondents was 53 years, and 61.8% self-identified as male. Twenty-four specialties were identified: 23.8% were from a primary care discipline and internal medicine represented the largest respondent group (12.1%).

Almost half of respondents (49.7%) worked in private practice, and 44.8% had been in practice for 21 years or longer.

Overall, 44.0% had at least one symptom of burnout, 38.8% of participants scored in the high range for emotional exhaustion, and 27.4% scored in the high range for depersonalization. The mean score in task load dimension varied by specialty.

The mean PTL score was 260.9 (standard deviation, 71.4). The specialties with the highest PTL score were emergency medicine (369.8), urology (353.7), general surgery subspecialties (343.9), internal medicine subspecialties (342.2), and radiology (341.6).

Aside from specialty, PTL scores also varied by practice setting, gender, age, number of hours worked per week, number of nights on call per week, and years in practice.

The researchers observed a dose response relationship between PTL and risk of burnout. For every 40-point (10%) reduction in PTL, there was 33% lower odds of experiencing burnout (odds ratio, 0.67; 95% confidence interval, 0.65-0.70; P < .0001). Multivariable analyses also indicated that PTL was a significant predictor of burnout, independent of practice setting, specialty, age, gender, and hours worked.
 

Organizational strategies to reduce physician burnout

Coauthors of the study, Tait D. Shanafelt, MD, professor of medicine at Stanford (Calif.) University and Colin P. West, MD, PhD, of the Mayo Clinic in Rochester, Minn., are both experts on physician well-being and are passionate about finding new ways to reduce physician distress and improving health care delivery.

“Authentic efforts to address this problem must move beyond personal resilience,” Dr. Shanafelt said in an interview. “Organizations that fail to get serious about this issue are going to be left behind and struggle in the war for talent.

“Much like our efforts to improve quality, advancing clinician well-being requires organizations to make it a priority and establish the structure, process, and leadership to promote the desired outcomes,” said Dr. Shanafelt.

One potential strategy for improvement is appointing a chief wellness officer, a dedicated individual within the health care system that leads the organizational effort, explained Dr. Shanafelt. “Over 30 vanguard institutions across the United States have already taken this step.”

Dr. West, a coauthor of the study, explained that conducting an analysis of PTL is fairly straightforward for hospitals and individual institutions. “The NASA-TLX tool is widely available, free to use, and not overly complex, and it could be used to provide insight into physician effort and mental, physical, and temporal demand levels,” he said in an interview.

“Deeper evaluations could follow to identify specific potential solutions, particularly system-level approaches to alleviate PTL,” Dr. West explained. “In the short term, such analyses and solutions would have costs, but helping physicians work more optimally and with less chronic strain from excessive task load would save far more than these costs overall.”

Dr. West also noted that physician burnout is very expensive to a health care system, and strategies to promote physician well-being would be a prudent financial decision long term for health care organizations.

Dr. Harry, lead author of the study, agreed with Dr. West, noting that “quality improvement literature has demonstrated that improvements in inefficiencies that lead to increased demand in the workplace often has the benefit of reduced cost.

“Many studies have demonstrated the risk of turnover due to burnout and the significant cost of physician turn over,” she said in an interview. “This cost avoidance is well worth the investment in improved operations to minimize unnecessary task load.”

Dr. Harry also recommended the NASA-TLX tool as a free resource for health systems and organizations. She noted that future studies will further validate the reliability of the tool.

“At the core, we need to focus on system redesign at both the micro and the macro level,” Dr. Harry said. “Each health system will need to assess inefficiencies in their work flow, while regulatory bodies need to consider the downstream task load of mandates and reporting requirements, all of which contribute to more cognitive load.”

The study was supported by funding from the Stanford Medicine WellMD Center, the American Medical Association, and the Mayo Clinic department of medicine program on physician well-being. Coauthors Lotte N. Dyrbye, MD, and Dr. Shanafelt are coinventors of the Physician Well-being Index, Medical Student Well-Being Index, Nurse Well-Being, and Well-Being Index. Mayo Clinic holds the copyright to these instruments and has licensed them for external use. Dr. Dyrbye and Dr. Shanafelt receive a portion of any royalties paid to Mayo Clinic. All other authors reported no conflicts of interest.

Work load, not personal vulnerability, may be at the root of the current physician burnout crisis, a recent study has concluded.

The cutting-edge research utilized cognitive theory and work load analysis to get at the source of burnout among practitioners. The findings indicate that, although some institutions continue to emphasize personal responsibility of physicians to address the issue, it may be the amount and structure of the work itself that triggers burnout in doctors.

“We evaluated the cognitive load of a clinical workday in a national sample of U.S. physicians and its relationship with burnout and professional satisfaction,” wrote Elizabeth Harry, MD, SFHM, a hospitalist at the University of Colorado at Denver, Aurora and coauthors. The results were reported in the Joint Commission Journal on Quality and Patient Safety.

The researchers investigated whether task load correlated with burnout scores in a large national study of U.S. physicians from October 2017 to March 2018.

As the delivery of health care becomes more complex, physicians are charged with ever-increasing amount of administrative and cognitive tasks. Recent evidence indicates that this growing complexity of work is tied to a greater risk of burnout in physicians, compared with workers in other fields. Cognitive load theory, pioneered by psychologist Jonathan Sweller, identified limitations in working memory that humans depend on to carry out cognitive tasks. Cognitive load refers to the amount of working memory used, which can be reduced in the presence of external emotional or physiological stressors. While a potential link between cognitive load and burnout may seem self-evident, the correlation between the cognitive load of physicians and burnout has not been evaluated in a large-scale study until recently.

wutwhanfoto/Getty Images

Physician task load (PTL) was measured using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), a validated questionnaire frequently used to evaluate the cognitive load of work environments, including health care environments. Four domains (perception of effort and mental, physical, and temporal demands) were used to calculate the total PTL score.

Burnout was evaluated using the Emotional Exhaustion and Depersonalization scales of the Maslach Burnout Inventory, a validated tool considered the gold standard for measurement.

The survey sample consisted of physicians of all specialties and was assembled using the American Medical Association Physician Masterfile, an almost complete record of all U.S. physicians independent of AMA membership. All responses were anonymous and participation was voluntary.
 

Results

Among 30,456 physicians who received the survey, 5,197 (17.1%) responded. In total, 5,276 physicians were included in the analysis.

The median age of respondents was 53 years, and 61.8% self-identified as male. Twenty-four specialties were identified: 23.8% were from a primary care discipline and internal medicine represented the largest respondent group (12.1%).

Almost half of respondents (49.7%) worked in private practice, and 44.8% had been in practice for 21 years or longer.

Overall, 44.0% had at least one symptom of burnout, 38.8% of participants scored in the high range for emotional exhaustion, and 27.4% scored in the high range for depersonalization. The mean score in task load dimension varied by specialty.

The mean PTL score was 260.9 (standard deviation, 71.4). The specialties with the highest PTL score were emergency medicine (369.8), urology (353.7), general surgery subspecialties (343.9), internal medicine subspecialties (342.2), and radiology (341.6).

Aside from specialty, PTL scores also varied by practice setting, gender, age, number of hours worked per week, number of nights on call per week, and years in practice.

The researchers observed a dose response relationship between PTL and risk of burnout. For every 40-point (10%) reduction in PTL, there was 33% lower odds of experiencing burnout (odds ratio, 0.67; 95% confidence interval, 0.65-0.70; P < .0001). Multivariable analyses also indicated that PTL was a significant predictor of burnout, independent of practice setting, specialty, age, gender, and hours worked.
 

Organizational strategies to reduce physician burnout

Coauthors of the study, Tait D. Shanafelt, MD, professor of medicine at Stanford (Calif.) University and Colin P. West, MD, PhD, of the Mayo Clinic in Rochester, Minn., are both experts on physician well-being and are passionate about finding new ways to reduce physician distress and improving health care delivery.

“Authentic efforts to address this problem must move beyond personal resilience,” Dr. Shanafelt said in an interview. “Organizations that fail to get serious about this issue are going to be left behind and struggle in the war for talent.

“Much like our efforts to improve quality, advancing clinician well-being requires organizations to make it a priority and establish the structure, process, and leadership to promote the desired outcomes,” said Dr. Shanafelt.

One potential strategy for improvement is appointing a chief wellness officer, a dedicated individual within the health care system that leads the organizational effort, explained Dr. Shanafelt. “Over 30 vanguard institutions across the United States have already taken this step.”

Dr. West, a coauthor of the study, explained that conducting an analysis of PTL is fairly straightforward for hospitals and individual institutions. “The NASA-TLX tool is widely available, free to use, and not overly complex, and it could be used to provide insight into physician effort and mental, physical, and temporal demand levels,” he said in an interview.

“Deeper evaluations could follow to identify specific potential solutions, particularly system-level approaches to alleviate PTL,” Dr. West explained. “In the short term, such analyses and solutions would have costs, but helping physicians work more optimally and with less chronic strain from excessive task load would save far more than these costs overall.”

Dr. West also noted that physician burnout is very expensive to a health care system, and strategies to promote physician well-being would be a prudent financial decision long term for health care organizations.

Dr. Harry, lead author of the study, agreed with Dr. West, noting that “quality improvement literature has demonstrated that improvements in inefficiencies that lead to increased demand in the workplace often has the benefit of reduced cost.

“Many studies have demonstrated the risk of turnover due to burnout and the significant cost of physician turn over,” she said in an interview. “This cost avoidance is well worth the investment in improved operations to minimize unnecessary task load.”

Dr. Harry also recommended the NASA-TLX tool as a free resource for health systems and organizations. She noted that future studies will further validate the reliability of the tool.

“At the core, we need to focus on system redesign at both the micro and the macro level,” Dr. Harry said. “Each health system will need to assess inefficiencies in their work flow, while regulatory bodies need to consider the downstream task load of mandates and reporting requirements, all of which contribute to more cognitive load.”

The study was supported by funding from the Stanford Medicine WellMD Center, the American Medical Association, and the Mayo Clinic department of medicine program on physician well-being. Coauthors Lotte N. Dyrbye, MD, and Dr. Shanafelt are coinventors of the Physician Well-being Index, Medical Student Well-Being Index, Nurse Well-Being, and Well-Being Index. Mayo Clinic holds the copyright to these instruments and has licensed them for external use. Dr. Dyrbye and Dr. Shanafelt receive a portion of any royalties paid to Mayo Clinic. All other authors reported no conflicts of interest.

Work load, not personal vulnerability, may be at the root of the current physician burnout crisis, a recent study has concluded.

The cutting-edge research utilized cognitive theory and work load analysis to get at the source of burnout among practitioners. The findings indicate that, although some institutions continue to emphasize personal responsibility of physicians to address the issue, it may be the amount and structure of the work itself that triggers burnout in doctors.

“We evaluated the cognitive load of a clinical workday in a national sample of U.S. physicians and its relationship with burnout and professional satisfaction,” wrote Elizabeth Harry, MD, SFHM, a hospitalist at the University of Colorado at Denver, Aurora and coauthors. The results were reported in the Joint Commission Journal on Quality and Patient Safety.

The researchers investigated whether task load correlated with burnout scores in a large national study of U.S. physicians from October 2017 to March 2018.

As the delivery of health care becomes more complex, physicians are charged with ever-increasing amount of administrative and cognitive tasks. Recent evidence indicates that this growing complexity of work is tied to a greater risk of burnout in physicians, compared with workers in other fields. Cognitive load theory, pioneered by psychologist Jonathan Sweller, identified limitations in working memory that humans depend on to carry out cognitive tasks. Cognitive load refers to the amount of working memory used, which can be reduced in the presence of external emotional or physiological stressors. While a potential link between cognitive load and burnout may seem self-evident, the correlation between the cognitive load of physicians and burnout has not been evaluated in a large-scale study until recently.

wutwhanfoto/Getty Images

Physician task load (PTL) was measured using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), a validated questionnaire frequently used to evaluate the cognitive load of work environments, including health care environments. Four domains (perception of effort and mental, physical, and temporal demands) were used to calculate the total PTL score.

Burnout was evaluated using the Emotional Exhaustion and Depersonalization scales of the Maslach Burnout Inventory, a validated tool considered the gold standard for measurement.

The survey sample consisted of physicians of all specialties and was assembled using the American Medical Association Physician Masterfile, an almost complete record of all U.S. physicians independent of AMA membership. All responses were anonymous and participation was voluntary.
 

Results

Among 30,456 physicians who received the survey, 5,197 (17.1%) responded. In total, 5,276 physicians were included in the analysis.

The median age of respondents was 53 years, and 61.8% self-identified as male. Twenty-four specialties were identified: 23.8% were from a primary care discipline and internal medicine represented the largest respondent group (12.1%).

Almost half of respondents (49.7%) worked in private practice, and 44.8% had been in practice for 21 years or longer.

Overall, 44.0% had at least one symptom of burnout, 38.8% of participants scored in the high range for emotional exhaustion, and 27.4% scored in the high range for depersonalization. The mean score in task load dimension varied by specialty.

The mean PTL score was 260.9 (standard deviation, 71.4). The specialties with the highest PTL score were emergency medicine (369.8), urology (353.7), general surgery subspecialties (343.9), internal medicine subspecialties (342.2), and radiology (341.6).

Aside from specialty, PTL scores also varied by practice setting, gender, age, number of hours worked per week, number of nights on call per week, and years in practice.

The researchers observed a dose response relationship between PTL and risk of burnout. For every 40-point (10%) reduction in PTL, there was 33% lower odds of experiencing burnout (odds ratio, 0.67; 95% confidence interval, 0.65-0.70; P < .0001). Multivariable analyses also indicated that PTL was a significant predictor of burnout, independent of practice setting, specialty, age, gender, and hours worked.
 

Organizational strategies to reduce physician burnout

Coauthors of the study, Tait D. Shanafelt, MD, professor of medicine at Stanford (Calif.) University and Colin P. West, MD, PhD, of the Mayo Clinic in Rochester, Minn., are both experts on physician well-being and are passionate about finding new ways to reduce physician distress and improving health care delivery.

“Authentic efforts to address this problem must move beyond personal resilience,” Dr. Shanafelt said in an interview. “Organizations that fail to get serious about this issue are going to be left behind and struggle in the war for talent.

“Much like our efforts to improve quality, advancing clinician well-being requires organizations to make it a priority and establish the structure, process, and leadership to promote the desired outcomes,” said Dr. Shanafelt.

One potential strategy for improvement is appointing a chief wellness officer, a dedicated individual within the health care system that leads the organizational effort, explained Dr. Shanafelt. “Over 30 vanguard institutions across the United States have already taken this step.”

Dr. West, a coauthor of the study, explained that conducting an analysis of PTL is fairly straightforward for hospitals and individual institutions. “The NASA-TLX tool is widely available, free to use, and not overly complex, and it could be used to provide insight into physician effort and mental, physical, and temporal demand levels,” he said in an interview.

“Deeper evaluations could follow to identify specific potential solutions, particularly system-level approaches to alleviate PTL,” Dr. West explained. “In the short term, such analyses and solutions would have costs, but helping physicians work more optimally and with less chronic strain from excessive task load would save far more than these costs overall.”

Dr. West also noted that physician burnout is very expensive to a health care system, and strategies to promote physician well-being would be a prudent financial decision long term for health care organizations.

Dr. Harry, lead author of the study, agreed with Dr. West, noting that “quality improvement literature has demonstrated that improvements in inefficiencies that lead to increased demand in the workplace often has the benefit of reduced cost.

“Many studies have demonstrated the risk of turnover due to burnout and the significant cost of physician turn over,” she said in an interview. “This cost avoidance is well worth the investment in improved operations to minimize unnecessary task load.”

Dr. Harry also recommended the NASA-TLX tool as a free resource for health systems and organizations. She noted that future studies will further validate the reliability of the tool.

“At the core, we need to focus on system redesign at both the micro and the macro level,” Dr. Harry said. “Each health system will need to assess inefficiencies in their work flow, while regulatory bodies need to consider the downstream task load of mandates and reporting requirements, all of which contribute to more cognitive load.”

The study was supported by funding from the Stanford Medicine WellMD Center, the American Medical Association, and the Mayo Clinic department of medicine program on physician well-being. Coauthors Lotte N. Dyrbye, MD, and Dr. Shanafelt are coinventors of the Physician Well-being Index, Medical Student Well-Being Index, Nurse Well-Being, and Well-Being Index. Mayo Clinic holds the copyright to these instruments and has licensed them for external use. Dr. Dyrbye and Dr. Shanafelt receive a portion of any royalties paid to Mayo Clinic. All other authors reported no conflicts of interest.

Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, walked through a multiagency attack plan for halting the spread of three COVID-19 variants earlier this week.

As part of JAMA’s Q&A series with JAMA editor in chief Howard Bauchner, MD, Dr. Walensky referenced the blueprint she coathored with Anthony Fauci, MD, the nation’s top infectious disease expert, and Henry T. Walke, MD, MPH, of the CDC, which was published on Feb. 17 in JAMA.

In the viewpoint article, they explain that the Department of Health & Human Services has established the SARS-CoV-2 Interagency Group to improve coordination among the CDC, the National Institutes of Health, the Food and Drug Administration, the Biomedical Advanced Research and Development Authority, the Department of Agriculture, and the Department of Defense.

Dr. Walensky said the first objective is to reinforce vigilance regarding public health mitigation strategies to decrease the amount of virus that’s circulating.

As part of that strategy, she said, the CDC strongly urges against nonessential travel.

In addition, public health leaders are working on a surveillance system to better understand the SARS-CoV-2 variants. That will take ramping up genome sequencing of the SARS-CoV-2 virus and ensuring that sampling is geographically representative.

She said the CDC is partnering with state health labs to obtain about 750 samples every week and is teaming up with commercial labs and academic centers to obtain an interim target of 6,000 samples per week.

She acknowledged the United States “is not where we need to be” with sequencing but has come a long way since January. At that time, they were sequencing 250 samples every week; they are currently sequencing thousands each week.

Data analysis is another concern: “We need to be able to understand at the basic science level what the information means,” Dr. Walensky said.

Researchers aren’t sure how the variants might affect use of convalescent plasma or monoclonal antibody treatments. It is expected that 5% of persons who are vaccinated against COVID-19 will nevertheless contract the disease. Sequencing will help answer whether such persons who have been vaccinated and who subsequently contract the virus are among those 5% or whether have been infected by a variant that evades the vaccine.

Accelerating vaccine administration globally and in the United States is essential, Dr. Walensky said.

As of Feb. 17, 56 million doses had been administered in the United States.
 

Top three threats

She updated the numbers on the three biggest variant threats.

Regarding B.1.1.7, which originated in the United Kingdom, she said: “So far, we’ve had over 1,200 cases in 41 states.” She noted that the variant is likely to be about 50% more transmissible and 30% to 50% more virulent.

“So far, it looks like that strain doesn’t have any real decrease in susceptibility to our vaccines,” she said.

The strain from South Africa (B.1.351) has been found in 19 cases in the United States.

The P.1. variant, which originated in Brazil, has been identified in two cases in two states.
 

Outlook for March and April

Dr. Bauchner asked Dr. Walensky what she envisions for March and April. He noted that public optimism is high in light of the continued reductions in COVID-19 case numbers, hospitalizations, and deaths, as well as the fact that warmer weather is coming and that more vaccinations are on the horizon.

“While I really am hopeful for what could happen in March and April,” Dr. Walensky said, “I really do know that this could go bad so fast. We saw it in November. We saw it in December.”

CDC models have projected that, by March, the more transmissible B.1.1.7 strain is likely to be the dominant strain, she reiterated.

“I worry that it will be spring, and we will all have had enough,” Dr. Walensky said. She noted that some states are already relaxing mask mandates.

“Around that time, life will look and feel a little better, and the motivation for those who might be vaccine hesitant may be diminished,” she said.

Dr. Bauchner also asked her to weigh in on whether a third vaccine, from Johnson & Johnson (J&J), may soon gain FDA emergency-use authorization – and whether its lower expected efficacy rate may result in a tiered system of vaccinations, with higher-risk populations receiving the more efficacious vaccines.

Dr. Walensky said more data are needed before that question can be answered.

“It may very well be that the data point us to the best populations in which to use this vaccine,” she said.

In phase 3 data, the J&J vaccine was shown to be 72% effective in the United States for moderate to severe disease.

Dr. Walensky said it’s important to remember that the projected efficacy for that vaccine is higher than that for the flu shot as well as many other vaccines currently in use for other diseases.

She said it also has several advantages. The vaccine has less-stringent storage requirements, requires just one dose, and protects against hospitalization and death, although it’s less efficacious in protecting against contracting the disease.

“I think many people would opt to get that one if they could get it sooner,” she said.

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

Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, walked through a multiagency attack plan for halting the spread of three COVID-19 variants earlier this week.

As part of JAMA’s Q&A series with JAMA editor in chief Howard Bauchner, MD, Dr. Walensky referenced the blueprint she coathored with Anthony Fauci, MD, the nation’s top infectious disease expert, and Henry T. Walke, MD, MPH, of the CDC, which was published on Feb. 17 in JAMA.

In the viewpoint article, they explain that the Department of Health & Human Services has established the SARS-CoV-2 Interagency Group to improve coordination among the CDC, the National Institutes of Health, the Food and Drug Administration, the Biomedical Advanced Research and Development Authority, the Department of Agriculture, and the Department of Defense.

Dr. Walensky said the first objective is to reinforce vigilance regarding public health mitigation strategies to decrease the amount of virus that’s circulating.

As part of that strategy, she said, the CDC strongly urges against nonessential travel.

In addition, public health leaders are working on a surveillance system to better understand the SARS-CoV-2 variants. That will take ramping up genome sequencing of the SARS-CoV-2 virus and ensuring that sampling is geographically representative.

She said the CDC is partnering with state health labs to obtain about 750 samples every week and is teaming up with commercial labs and academic centers to obtain an interim target of 6,000 samples per week.

She acknowledged the United States “is not where we need to be” with sequencing but has come a long way since January. At that time, they were sequencing 250 samples every week; they are currently sequencing thousands each week.

Data analysis is another concern: “We need to be able to understand at the basic science level what the information means,” Dr. Walensky said.

Researchers aren’t sure how the variants might affect use of convalescent plasma or monoclonal antibody treatments. It is expected that 5% of persons who are vaccinated against COVID-19 will nevertheless contract the disease. Sequencing will help answer whether such persons who have been vaccinated and who subsequently contract the virus are among those 5% or whether have been infected by a variant that evades the vaccine.

Accelerating vaccine administration globally and in the United States is essential, Dr. Walensky said.

As of Feb. 17, 56 million doses had been administered in the United States.
 

Top three threats

She updated the numbers on the three biggest variant threats.

Regarding B.1.1.7, which originated in the United Kingdom, she said: “So far, we’ve had over 1,200 cases in 41 states.” She noted that the variant is likely to be about 50% more transmissible and 30% to 50% more virulent.

“So far, it looks like that strain doesn’t have any real decrease in susceptibility to our vaccines,” she said.

The strain from South Africa (B.1.351) has been found in 19 cases in the United States.

The P.1. variant, which originated in Brazil, has been identified in two cases in two states.
 

Outlook for March and April

Dr. Bauchner asked Dr. Walensky what she envisions for March and April. He noted that public optimism is high in light of the continued reductions in COVID-19 case numbers, hospitalizations, and deaths, as well as the fact that warmer weather is coming and that more vaccinations are on the horizon.

“While I really am hopeful for what could happen in March and April,” Dr. Walensky said, “I really do know that this could go bad so fast. We saw it in November. We saw it in December.”

CDC models have projected that, by March, the more transmissible B.1.1.7 strain is likely to be the dominant strain, she reiterated.

“I worry that it will be spring, and we will all have had enough,” Dr. Walensky said. She noted that some states are already relaxing mask mandates.

“Around that time, life will look and feel a little better, and the motivation for those who might be vaccine hesitant may be diminished,” she said.

Dr. Bauchner also asked her to weigh in on whether a third vaccine, from Johnson & Johnson (J&J), may soon gain FDA emergency-use authorization – and whether its lower expected efficacy rate may result in a tiered system of vaccinations, with higher-risk populations receiving the more efficacious vaccines.

Dr. Walensky said more data are needed before that question can be answered.

“It may very well be that the data point us to the best populations in which to use this vaccine,” she said.

In phase 3 data, the J&J vaccine was shown to be 72% effective in the United States for moderate to severe disease.

Dr. Walensky said it’s important to remember that the projected efficacy for that vaccine is higher than that for the flu shot as well as many other vaccines currently in use for other diseases.

She said it also has several advantages. The vaccine has less-stringent storage requirements, requires just one dose, and protects against hospitalization and death, although it’s less efficacious in protecting against contracting the disease.

“I think many people would opt to get that one if they could get it sooner,” she said.

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

Rochelle Walensky, MD, MPH, director of the Centers for Disease Control and Prevention, walked through a multiagency attack plan for halting the spread of three COVID-19 variants earlier this week.

As part of JAMA’s Q&A series with JAMA editor in chief Howard Bauchner, MD, Dr. Walensky referenced the blueprint she coathored with Anthony Fauci, MD, the nation’s top infectious disease expert, and Henry T. Walke, MD, MPH, of the CDC, which was published on Feb. 17 in JAMA.

In the viewpoint article, they explain that the Department of Health & Human Services has established the SARS-CoV-2 Interagency Group to improve coordination among the CDC, the National Institutes of Health, the Food and Drug Administration, the Biomedical Advanced Research and Development Authority, the Department of Agriculture, and the Department of Defense.

Dr. Walensky said the first objective is to reinforce vigilance regarding public health mitigation strategies to decrease the amount of virus that’s circulating.

As part of that strategy, she said, the CDC strongly urges against nonessential travel.

In addition, public health leaders are working on a surveillance system to better understand the SARS-CoV-2 variants. That will take ramping up genome sequencing of the SARS-CoV-2 virus and ensuring that sampling is geographically representative.

She said the CDC is partnering with state health labs to obtain about 750 samples every week and is teaming up with commercial labs and academic centers to obtain an interim target of 6,000 samples per week.

She acknowledged the United States “is not where we need to be” with sequencing but has come a long way since January. At that time, they were sequencing 250 samples every week; they are currently sequencing thousands each week.

Data analysis is another concern: “We need to be able to understand at the basic science level what the information means,” Dr. Walensky said.

Researchers aren’t sure how the variants might affect use of convalescent plasma or monoclonal antibody treatments. It is expected that 5% of persons who are vaccinated against COVID-19 will nevertheless contract the disease. Sequencing will help answer whether such persons who have been vaccinated and who subsequently contract the virus are among those 5% or whether have been infected by a variant that evades the vaccine.

Accelerating vaccine administration globally and in the United States is essential, Dr. Walensky said.

As of Feb. 17, 56 million doses had been administered in the United States.
 

Top three threats

She updated the numbers on the three biggest variant threats.

Regarding B.1.1.7, which originated in the United Kingdom, she said: “So far, we’ve had over 1,200 cases in 41 states.” She noted that the variant is likely to be about 50% more transmissible and 30% to 50% more virulent.

“So far, it looks like that strain doesn’t have any real decrease in susceptibility to our vaccines,” she said.

The strain from South Africa (B.1.351) has been found in 19 cases in the United States.

The P.1. variant, which originated in Brazil, has been identified in two cases in two states.
 

Outlook for March and April

Dr. Bauchner asked Dr. Walensky what she envisions for March and April. He noted that public optimism is high in light of the continued reductions in COVID-19 case numbers, hospitalizations, and deaths, as well as the fact that warmer weather is coming and that more vaccinations are on the horizon.

“While I really am hopeful for what could happen in March and April,” Dr. Walensky said, “I really do know that this could go bad so fast. We saw it in November. We saw it in December.”

CDC models have projected that, by March, the more transmissible B.1.1.7 strain is likely to be the dominant strain, she reiterated.

“I worry that it will be spring, and we will all have had enough,” Dr. Walensky said. She noted that some states are already relaxing mask mandates.

“Around that time, life will look and feel a little better, and the motivation for those who might be vaccine hesitant may be diminished,” she said.

Dr. Bauchner also asked her to weigh in on whether a third vaccine, from Johnson & Johnson (J&J), may soon gain FDA emergency-use authorization – and whether its lower expected efficacy rate may result in a tiered system of vaccinations, with higher-risk populations receiving the more efficacious vaccines.

Dr. Walensky said more data are needed before that question can be answered.

“It may very well be that the data point us to the best populations in which to use this vaccine,” she said.

In phase 3 data, the J&J vaccine was shown to be 72% effective in the United States for moderate to severe disease.

Dr. Walensky said it’s important to remember that the projected efficacy for that vaccine is higher than that for the flu shot as well as many other vaccines currently in use for other diseases.

She said it also has several advantages. The vaccine has less-stringent storage requirements, requires just one dose, and protects against hospitalization and death, although it’s less efficacious in protecting against contracting the disease.

“I think many people would opt to get that one if they could get it sooner,” she said.

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