MDedge Cardiology

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.

If you have had the chance to watch any TV over the last 6 months, you have probably seen the commercials for home devices that allow patients to quickly check for atrial fibrillation in the comfort of their own home.

In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.

KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.

The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
 

How effective is KardiaMobile at detecting AFib?

Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.¹ In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.²

How does the Apple Watch find AFib?

Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.

The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.

In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.³ Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.^4,5
 

^{What should we do with the results?}

It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.

While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

References

1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.

2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.

3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.

4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.

5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.

If you have had the chance to watch any TV over the last 6 months, you have probably seen the commercials for home devices that allow patients to quickly check for atrial fibrillation in the comfort of their own home.

In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.

KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.

The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
 

How effective is KardiaMobile at detecting AFib?

Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.¹ In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.²

How does the Apple Watch find AFib?

Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.

The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.

In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.³ Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.^4,5
 

^{What should we do with the results?}

It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.

While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

References

1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.

2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.

3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.

4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.

5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.

If you have had the chance to watch any TV over the last 6 months, you have probably seen the commercials for home devices that allow patients to quickly check for atrial fibrillation in the comfort of their own home.

In an ad for one of these products, KardiaMobile, a cardiologist says this device “detects atrial fibrillation, one of the major causes of stroke.” You might also have heard that the Apple Watch has an opt-in feature that constantly screens for atrial fibrillation without any effort being made by the patient, or can check on-demand for AFib if a wearer experiences palpitations or an abnormal heart beat. Both of these devices generate a standard limb–lead ECG (essentially lead I) by connecting the device to both arms and producing a 30-second rhythm strip.

KardiaMobile recently introduced a newer device. When you place this device on a bare knee and touch one electrode with fingers from the right hand and another electrode with fingers from the left hand, the device produces a six-lead ECG. These small devices send an image of the ECG to a patient’s smartphone over Bluetooth, and the results can be easily read, printed out, or sent to the doctor for further analysis. Additionally, both of KardiaMobile’s devices utilize artificial intelligence to analyze a rhythm strip in real time and let the patient know if the ECG is normal, shows AFib, or is unable to be analyzed.

The electrocardiographic technology was formerly only available in a medical setting. It required an expensive machine and could only be interpreted by someone with expertise developed through years of training. Now it is readily available to patients in their homes. But how accurate is the technology and how are we going to use it?
 

How effective is KardiaMobile at detecting AFib?

Studies have looked at both KardiaMobile and the Apple Watch. One study of KardiaMobile in patients with Afib who were admitted for antiarrhythmic drug initiation showed that about a quarter of readings could not be classified because of artifact and other reasons. After exclusion of unclassified recordings, the KardiaMobile interpretation had 97% sensitivity and 94% specificity for AFib detection when compared with physician-interpreted ECGs.¹ In a large review of the device’s accuracy, there was about 85% sensitivity and specificity of the automated readings.²

How does the Apple Watch find AFib?

Like the KardiaMobile device, the Apple Watch can be used whenever patients notice symptoms or whenever they and their physicians decide the device would be useful. In addition, though, the Apple Watch has a function where the wearer can opt in to have the watch screen for AFib in the background whenever the watch is worn.

The watch monitors heart rate using photoplethysmography, where light-sensitive photodiodes detect blood pulses to assess heart rate variability. When an irregular heart rate is detected, the AW alerts the user of possible AFib. Once alerted, the wearer can then utilize a second function to obtain a single-lead ECG. Heart rate, rhythm, and a 30-second ECG tracing are saved in the Bluetooth-linked iPhone’s health app and can be exported for review by a physician.

In a study of over 400,000 participants, among participants notified of an irregular pulse through screening there was a positive predictive value of 84%.³ Single-lead EKGs initiated by watch wearers had a specificity for AFib of 99.6% among tracings with good wave forms, indicating very few false positives. Only 1 individual of the 263 individuals who had normal sinus rhythm on 12-lead ECG was classified as having AFib, though in 7% sinus rhythm could not be confirmed because of poor tracings.^4,5
 

^{What should we do with the results?}

It’s impressive that these devices deliver accurate information with very good specificity. Our hope is that detecting AFib with one of these devices will lead to an intervention being made that will decrease a patient’s risk of stroke. But it is not clear if routine screening in asymptomatic adults will accomplish this.

While more data is needed, we must acknowledge that our patients will soon be bringing us results from home. Regardless of what we think of this technology, we need to decide what to do when patients call us with results from these devices.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Follow him on Twitter (@doctornotte). Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

References

1. William A et al. Heart Rhythm. 2018 Oct;15(10):1561-5.

2. KardiaMobile for the ambulatory detection of atrial fibrillation. NICE Medtech innovation briefing. 29 October 2020 Oct 29. www.nice.org.uk/guidance/mib232.

3. Perez MV et al. N Engl J Med. 2019; 381:1909-17.

4. Using Apple Watch for Arrhythmia Detection, December 2018. Apple. https://www.apple.com/healthcare/site/docs/Apple_Watch_Arrhythmia_Detection.pdf. Accessed 2019 Apr 5.

5. De Novo Classification Request for ECG App. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN180044.pdf. Accessed 2019 Apr 29.

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.

The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.

The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.

The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.

Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.

There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.

For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
 

Revascularization uncertainty

Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.

Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.

“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.

What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”

The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”

Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.

That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
 

Coding not in sync with UDMI

If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.

For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.

“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.

Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”

In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”

“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
 

Most type 2 MI is a complication

A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).

Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.

Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.

In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.

In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.

“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”

Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
 

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

The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.

The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.

The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.

Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.

There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.

For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
 

Revascularization uncertainty

Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.

Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.

“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.

What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”

The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”

Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.

That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
 

Coding not in sync with UDMI

If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.

For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.

“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.

Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”

In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”

“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
 

Most type 2 MI is a complication

A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).

Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.

Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.

In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.

In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.

“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”

Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
 

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

The hospital and postdischarge course of patients diagnosed with type 2 myocardial infarction, triggered when myocardial oxygen demand outstrips supply, differs in telling ways from those with the more common atherothrombotic type 1 MI, suggests a new registry analysis that aims to lift a cloud of confusion surrounding their management.

The observational study of more than 250,000 patients with either form of MI, said to be the largest of its kind, points to widespread unfamiliarity with distinctions between the two, and the diagnostic and therapeutic implications of misclassification. It suggests, in particular, that type 2 MI may be grossly underdiagnosed and undertreated.

The minority of patients with type 2 MI were more likely female and to have heart failure (HF), renal disease, valve disease, or atrial fibrillation, and less likely to have a lipid disorder, compared with those with type 1 MI. They were one-fifth as likely to be referred for coronary angiography and 20 times less likely to undergo revascularization.

Indeed, only about 2% of the type 2 cohort ultimately underwent percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG). Yet the analysis suggests that cardiovascular risk climbs regardless of MI type and that in patients with type 2 MI, coronary revascularization might well cut the risk of death in half over the short term.

There were also disparities in clinical outcomes in the analysis, based on data from the final 3 months of 2017 in the Nationwide Readmissions Database, which reportedly documents almost 60% of hospitalizations in the United States.

For example, those with type 1 or type 2 MI – as characterized in the then-current third Universal Definition of Myocardial Infarction and today’s UDMI-4 – were comparably at risk for both 30-day all-cause readmission and HF readmission. But type 2 patients were less likely to die in the hospital or be readmitted within 30 days for recurrent MI.
 

Revascularization uncertainty

Importantly, the study’s 3-month observation period immediately followed the debut of a code specifically for type 2 MI in the ICD-10-CM system.

Type 2 accounted for about 15% of MIs during that period, the percentage climbing sharply from the first to the third month. That suggests clinicians were still getting used to the code during the early weeks, “undercoding” for type-2 MI at first but less so after some experience, Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston, said in an interview.

“I can imagine that as people become more aware of the coding, using it more often, the proportion of type 2 MI relative to the total MI cases will probably be much higher,” said McCarthy, lead author on the study published online Feb. 15, 2021, in the Journal of the American College of Cardiology.

What had been understood about type 2 MI came largely from single-center studies, he said. This “first national study of type-2 MI in the United States” sought to determine whether such findings are hospital specific or “representative of what people are doing nationally.”

The new analysis largely confirms that patients with type 2 MI are typically burdened with multiple comorbidities, Dr. McCarthy said, but also suggests that type 2 often was, and likely still is, incorrectly classified as type 1. So, it was “surprising” that they were rarely referred for angiography. “Only 1 in 50 received revascularization.”

Those diagnosed with type-2 MI were far less likely to receive coronary angiography (10.9% vs. 57.3%), PCI (1.7% vs. 38.5%), or CABG (0.4% vs. 7.8%) (P < .001 for all three differences), the report noted.

That, Dr. McCarthy said, “clearly shows that clinicians are uncertain about whether revascularization is beneficial” in type 2 MI.
 

Coding not in sync with UDMI

If there is confusion in practice about differentiating type 2 from type 1 MI, it likely has multiple sources, and one may be inconsistencies in how the UDMI and relevant ICD codes are applied in practice.

For example, the coding mandate is always to classify ST-segment elevation MI and non-STEMI as type 1, yet UDMI-4 itself states that a type 2 MI may be either STEMI or non-STEMI, noted Dr. McCarthy, as well as an editorial accompanying the report.

“It also can be difficult at times to distinguish type 2 MI from the diagnosis of myocardial injury,” both of which are partly defined by elevated cardiac troponin (cTn), adds the editorial, from Kristian Thygesen, MD, DSc, Aarhus (Denmark) University Hospital, Aarhus, Denmark, and Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minn.

Crucially, but potentially sometimes overlooked, a diagnosis of infarction requires evidence of ischemia along with the biomarker elevation, whereas myocardial injury is defined by raised cTn without evidence of ischemia. Yet there is no ICD-10-CM code for “nonischemic myocardial injury,” Dr. Thygesen and Dr. Jaffe observed.

“Instead, the new ICD-10-CM coding includes a proxy called ‘non-MI troponin elevation due to an underlying cause,’ ” they wrote. “Unfortunately, although some have advocated using this code for myocardial injury, it is not specific for an elevated cTn value and could represent any abnormal laboratory measurements.” The code could be “misleading” and thus worsen the potential for miscoding and “misattribution of MI diagnoses.”

In the current study, 84.6% of the cohort were classified with type 1 MI, 14.8% with type 2, and 0.6% with both types. Of those with type 1 MI, 22.1% had STEMI, 76.4% had non-STEMI with the remainder “unspecified.”

“I think the introduction of ICD codes for type-2 MI is helpful in that we can study type 2 MI more broadly, across institutions, and try and get a better sense of its outcomes and how these patients are treated,” Dr. McCarthy said. But the coding system’s deficiencies may often lead to misclassification of patients. Especially, patients with type 2 STEMI may be miscoded as having type-1 STEMI, and those with only myocardial injury may be miscoded as having type 2 MI.
 

Most type 2 MI is a complication

A profile of patients with type 2 MI may be helpful for making distinctions. The analysis showed that, compared with patients with type 1 MI, they were slightly but significantly older and more likely to have clinical depression, alcohol or other substance abuse disorder, and to be female. They also had more heart failure (27.9% vs. 10.9%), kidney disease (35.7% vs. 25.7%), atrial fibrillation (31% vs. 21%), and anemia (26% vs. 18.9%) (P < .001 for all differences).

Type 2 patients were less likely to have CV risk factors usually associated with plaque instability and atherothrombosis, including a history of smoking, dyslipidemia, MI, PCI, or CABG (P < .001 for all differences), the group noted.

Of the 37,765 patients with type 2 MI, 91% received the diagnosis as secondary to another condition, including sepsis in 24.5%, hypertension in 16.9%, arrhythmias in 6.1%, respiratory failure in 4.3%, and pneumonia in 2.8% of cases.

In multivariate analyses, patients with type 2 MI, compared with type 1, showed lower risks of in-hospital death and readmission for MI within 30 days. Their 30-day risks of readmission from any cause and from MI were similar.

In-hospital mortality was lower for patients with type 2 MI who underwent revascularization, compared with those who did not, “but they were a very select, small proportion of the patient group. I would say there are probably unmeasured confounders,” Dr. McCarthy said.

“There’s a real kind of equipoise, so I think we desperately need a trial to guide us on whether revascularization is beneficial.”

Dr. McCarthy has disclosed no relevant financial relationships. Dr. Thygesen disclosed no relevant financial relationships. Dr. Jaffe disclosed serving as a consultant for Abbott, Roche, Siemens, Beckman-Coulter, Radiometer, ET Healthcare, Sphingotec, Brava, Quidel, Amgen, Novartis, and Medscape for educational activities.
 

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

Long-term use of continuous positive airway pressure (CPAP) was associated with higher self-reported physical activity levels in adults with co-occurring obstructive sleep apnea (OSA) and cardiovascular disease (CVD), in new research.

“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.

Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.

Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
 

Moderate physical activity was higher among CPAP users

After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).

However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).

In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.

“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.

“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.

The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.

They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
 

Study reinforces CPAP’s health benefits

Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.

“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.

Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.

“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”

The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.

Long-term use of continuous positive airway pressure (CPAP) was associated with higher self-reported physical activity levels in adults with co-occurring obstructive sleep apnea (OSA) and cardiovascular disease (CVD), in new research.

“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.

Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.

Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
 

Moderate physical activity was higher among CPAP users

After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).

However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).

In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.

“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.

“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.

The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.

They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
 

Study reinforces CPAP’s health benefits

Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.

“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.

Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.

“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”

The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.

Long-term use of continuous positive airway pressure (CPAP) was associated with higher self-reported physical activity levels in adults with co-occurring obstructive sleep apnea (OSA) and cardiovascular disease (CVD), in new research.

“The aim of this study was to determine whether long-term CPAP treatment affects self-reported physical activity among participants with moderate-severe OSA and comorbid CV disease,” wrote David Stevens, PhD, of Flinders University, Adelaide, Australia, and his colleagues. The findings were recently published in the Journal of Clinical Sleep Medicine.

Researchers conducted a secondary analysis of the Sleep apnea cardiovascular endpoints (SAVE) trial that enrolled 2,687 adults aged 45-75 years old with OSA and confirmed CVD. In the study, participants were randomized to receive either CPAP plus usual care or usual care alone.

Physical activity levels were self-reported using the Leisure-Time Exercise Questionnaire (LTEQ) at baseline and at 6-, 24-, and 48-month follow-up intervals. The physical functioning subscale of the 36-item short form questionnaire (SF-36) was used to determine if activity levels were consistent with expert recommendations and to evaluate the effects on any self-perceived limitation of physical activity.
 

Moderate physical activity was higher among CPAP users

After a mean follow-up duration of 3.7 years, participants in the CPAP arm had approximately 20% higher levels of moderate physical activity, compared with the control arm (adjusted mean scores]: 8.7 points vs. 7.3 points; 95% confidence interval, 7.5-9.9 vs. 6.1-8.5; P = .003).

However, no significant difference was observed between treatment arms for mild physical activity (adjusted mean scores, 14.4 points vs. 14.2 points; 95% CI, 13.5-15.3 vs. 13.3-15.1; P = 0.599) or vigorous physical activity (adjusted mean scores, 3.4 points vs. 2.9 points; 95% CI 2.6-4.2 vs. 2.1-3.7; P = .125).

In addition, participants in the CPAP group reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score = 1.66; 95% CI, 0.87-2.45; P < .001) and were more likely to report activity levels consistent with guideline recommendations.

“We were pleasantly surprised to find that people assigned to CPAP reported more physical activity than their counterparts who received usual care, despite being given no specific exercise instructions,” Kelly A. Loffler, PhD, a coauthor of the study, said in an interview.

“While I don’t think this will result in any immediate changes to guidelines, it is a helpful reminder to clinicians who are treating such patients, that the symptomatic benefits people experience with CPAP present a window of opportunity to improve health more holistically,” Dr. Loffler explained.

The researchers acknowledged that a key limitation of the study was the use of self-reported outcome measures. In future studies, they recommended that recent technological innovations, such as the availability of activity tracking devices, should be used to measure physical activity.

They also noted that patients with excessive sleepiness and severe hypoxemia were excluded from the SAVE trial; thus, the findings may not be generalizable to all patients.
 

Study reinforces CPAP’s health benefits

Emerson M. Wickwire, PhD, associate professor of psychiatry and medicine at the University of Maryland, Baltimore, explained that CPAP treatment is associated with well-documented health benefits among patients with CVD, as well as enhanced quality of life.

“These results provide further evidence that treating OSA can provide direct and indirect health benefits, suggesting that increased physical activity can be a vital pathway to improved cardiovascular health and enjoyment of life,” Dr. Wickwire, who is also director of the Insomnia Program at the University of Maryland Midtown Medical Center, Baltimore, said in an interview.

Steven M. Scharf, MD, a pulmonologist who is director of the Sleep Disorders Center (Adults) at the University of Maryland, also said the study findings were consistent with previous research involving patients treated for OSA.

“It is no surprise that treatment of OSA improves patient’s daily physical functioning,” explained Dr. Scharf, who is also a clinical professor, in an interview. “These results are expected, but very welcome, and I was glad to see them.”

The study was funded by the National Health and Medical Research Council of Australia, the Respironics Sleep and Respiratory Research Foundation, and Philips Respironics. Some authors reported financial affiliations with medical device and pharmaceutical companies. Dr. Loffler, Dr. Wickwire, and Dr. Scharf reported no conflicts of interest related to this work.

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.

[email protected]

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.

[email protected]

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.

[email protected]

The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.

Pheelings Media/Getty Images

Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).

“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.

Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”

POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
 

A COVID connection?

The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.

“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”

Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”

There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.

Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.

The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.

A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.

Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.

Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).

“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”

Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.

In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”

Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”

Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.  

“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.

Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.

The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.

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

The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.

Pheelings Media/Getty Images

Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).

“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.

Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”

POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
 

A COVID connection?

The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.

“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”

Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”

There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.

Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.

The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.

A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.

Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.

Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).

“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”

Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.

In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”

Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”

Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.  

“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.

Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.

The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.

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

The heart failure drug ivabradine (Corlanor) can provide relief from the elevated heart rate and often debilitating symptoms associated with postural orthostatic tachycardia syndrome (POTS), a new study suggests.

Pheelings Media/Getty Images

Ivabradine significantly lowered standing heart rate, compared with placebo (77.9 vs. 94.2 beats/min; P < .001). The typical surge in heart rate that occurs upon standing in these patients was also blunted, compared with baseline (13.0 vs. 21.4 beats/min; P = .001).

“There are really not a lot of great options for patients with POTS and, mechanistically, ivabradine just make sense because it’s a drug that lowers heart rate very selectively and doesn’t lower blood pressure,” lead study author Pam R. Taub, MD, told this news organization.

Surprisingly, the reduction in heart rate translated into improved physical (P = .008) and social (P = .021) functioning after just 1 month of ivabradine, without any other background POTS medications or a change in nonpharmacologic therapies, she said. “What’s really nice to see is when you tackle a really significant part of the disease, which is the elevated heart rate, just how much better they feel.”

POTS patients are mostly healthy, active young women, who after some inciting event – such as viral infection, trauma, or surgery – experience an increase in heart rate of at least 30 beats/min upon standing accompanied by a range of symptoms, including dizziness, palpitations, brain fog, and fatigue.
 

A COVID connection?

The study enrolled patients with hyperadrenergic POTS as the predominant subtype, but another group to keep in mind that might benefit is the post-COVID POTS patient, said Dr. Taub, from the University of California, San Diego.

“We’re seeing an incredible number of patients post COVID that meet the criteria for POTS, and a lot of these patients also have COVID fatigue,” she said. “So clinically, myself and many other cardiologists who understand ivabradine have been using it off-label for the COVID patients, as long as they meet the criteria. You don’t want to use it in every COVID patient, but if someone’s predominant complaint is that their heart rate is going up when they’re standing and they’re debilitated by it, this is a drug to consider.”

Anecdotal findings in patients with long-hauler COVID need to be translated into rigorous research protocols, but mechanistically, whether it’s POTS from COVID or from another type of infection – like Lyme disease or some other viral syndrome – it should work the same, Dr. Taub said. “POTS is POTS.”

There are no first-line drugs for POTS, and current class IIb recommendations include midodrine, which increases blood pressure and can make people feel awful, and fludrocortisone, which can cause a lot of weight gain and fluid retention, she observed. Other agents that lower heart rate, like beta-blockers, also lower blood pressure and can aggravate depression and fatigue.

Ivabradine regulates heart rate by specifically blocking the Ifunny channel of the sinoatrial node. It was approved in 2015 in the United States to reduce hospitalizations in patients with systolic heart failure, and it also has a second class IIb recommendation for inappropriate sinus tachycardia.

The present study, reported in the Feb. 23 issue of the Journal of the American College of Cardiology, is the first randomized clinical trial using ivabradine to treat POTS.

A total of 26 patients with POTS were started on ivabradine 5 mg or placebo twice daily for 1 month, then were crossed over to the other treatment for 1 month after a 1-week washout period. Six patients were started on a 2.5-mg twice-daily dose. Doses were adjusted during the study based on the patient’s heart rate response and tolerance. Patients had seven clinic visits in which norepinephrine (NE) levels were measured and head-up tilt testing conducted.

Four patients in the ivabradine arm withdrew because of adverse effects, and one withdrew during crossover.

Among the 22 patients who completed the study, exploratory analyses showed a strong trend for greater reduction in plasma NE upon standing with ivabradine (P = .056). The effect was also more profound in patients with very high baseline standing NE levels (at least 1,000 pg/mL) than in those with lower NE levels (600 to 1,000 pg/mL).

“It makes sense because that means their sympathetic nervous system is more overactive; they have a higher heart rate,” Dr. Taub said. “So it’s a potential clinical tool that people can use in their practice to determine, ‘okay, is this a patient I should be considering ivabradine on?’ ”

Although the present study had only 22 patients, “it should definitely be looked at as a step forward, both in terms of ivabradine specifically and in terms of setting the standard for the types of studies we want to see in our patients,” Satish R. Raj, MD, MSCI, University of Calgary (Alta.), said in an interview.

In a related editorial, however, Dr. Raj and coauthor Robert S. Sheldon, MD, PhD, also from the University of Calgary, point out that the standing heart rate in the placebo phase was only 94 beats/min, “suggesting that these patients may be affected only mildly by their POTS.”

Asked about the point, Dr. Taub said: “I don’t know if I agree with that.” She noted that the diagnosis of POTS was confirmed by tilt-table testing and NE levels and that patients’ symptoms vary from day to day. “The standard deviation was plus or minus 16.8, so there’s variability.”

Both Dr. Raj and Dr. Taub said they expect the results will be included in the next scientific statement for POTS, but in the meantime, it may be a struggle to get the drug covered by insurance.  

“The challenge is that this is a very off-label use for this medication, and the medication’s not cheap,” Dr. Raj observed. The price for 60 tablets, which is about a 1-month supply, is $485 on GoodRx.

Another question going forward, he said, is whether ivabradine is superior to beta-blockers, which will be studied in a 20-patient crossover trial sponsored by the University of Calgary that is about to launch. The primary completion date is set for 2024.

The study was supported by a grant from Amgen. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA. Dr. Raj has received a research grant from the Canadian Institutes of Health Research and research grants from Dysautonomia International to address the pathophysiology of POTS. Dr. Sheldon has received a research grant from Dysautonomia International for a clinical trial assessing ivabradine and propranolol for the treatment of POTS.

A version of this article first appeared on Medscape.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.