Federal Practitioner

A new analysis projects steep increases by 2060 in the prevalence of cardiovascular (CV) risk factors and disease that will disproportionately affect non-White populations who have limited access to health care.

The study by Reza Mohebi, MD, Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues was published in the Journal of the American College of Cardiology.

“Even though several assumptions underlie these projections, the importance of this work cannot be overestimated,” Andreas P. Kalogeropoulos, MD, MPH, PhD, and Javed Butler, MD, MPH, MBA, wrote in an accompanying editorial. “The absolute numbers are staggering.”

From 2025 to 2060, the number of people with any one of four CV risk factors – type 2 diabetes, hypertension, dyslipidemia, and obesity – is projected to increase by 15.4 million, to 34.7 million.

And the number of people with of any one of four CV disease types – ischemic heart disease, heart failure, MI, and stroke – is projected to increase by 3.2 million, to 6.8 million.

Although the model predicts that the prevalence of CV risk factors will gradually decrease among White Americans, the highest prevalence of CV risk factors will be among the White population because of its overall size.

Conversely, the projected prevalence of CV risk factors is expected to increase in Black, Hispanic, Asian, and other race/ethnicity populations.

In parallel, the prevalence of CV disease is projected to decrease in the White population and increase among all other race/ethnicities, particularly in the Black and Hispanic populations.

Courtesy Massachusetts General Hospital

“Our results project a worrisome increase with a particularly ominous increase in risk factors and disease in our most vulnerable patients, including Blacks and Hispanics,” senior author James L. Januzzi Jr., MD, summarized in a video issued by the society.

“The steep rise in CV risk factors and disease reflects the generally higher prevalence in populations projected to increase in the United States, owing to immigration and growth, including Black or Hispanic individuals,” Dr. Januzzi, also from Massachusetts General and Harvard, said in an interview.

“The disproportionate size of the risk is expected in a sense, as minority populations are disproportionately disadvantaged with respect to their health care,” he said. “But whether it is expected or not, the increase in projected prevalence is, nonetheless, concerning and a call to action.”

This study identifies “areas of opportunity for change in the U.S. health care system,” he continued. “Business as usual will result in us encountering a huge number of individuals with CV risk factors and diseases.”

The results from the current analysis assume there will be no modification in health care policies or changes in access to care for at-risk populations, Dr. Mohebi and colleagues noted.

To “stem the rising tide of CV disease in at-risk individuals,” would require strategies such as “emphasis on education regarding CV risk factors, improving access to quality healthcare, and facilitating lower-cost access to effective therapies for treatment of CV risk factors,” according to the researchers.

“Such advances need to be applied in a more equitable way throughout the United States, however,” they cautioned.
 

Census plus NHANES data

The researchers used 2020 U.S. census data and projected growth and 2013-2018 U.S. National Health and Nutrition Survey data to estimate the number of people with CV risk factors and CV disease from 2025 to 2060.

The estimates are based on a growing population and a fixed frequency.

Changing demographic landscape

It is “striking” that the numbers of non-White individuals with CV risk factors is projected to surpass the number of White individuals over time, and the number of non-White individuals with CV disease will be almost as many as White individuals by the year 2060, the editorialists noted.

“From a policy perspective, this means that unless appropriate, targeted action is taken, disparities in the burden of cardiovascular disease are only going to be exacerbated over time,” wrote Dr. Kalogeropoulos, from Stony Brook (N.Y.) University, and Dr. Butler, from Baylor College of Medicine, Dallas.

“On the positive side,” they continued, “the absolute increase in the percent prevalence of cardiovascular risk factors and conditions is projected to lie within a manageable range,” assuming that specific prevention policies are implemented.

“This is an opportunity for professional societies, including the cardiovascular care community, to re-evaluate priorities and strategies, for both training and practice, to best match the growing demands of a changing demographic landscape in the United States,” Dr. Kalogeropoulos and Dr. Butler concluded.

Dr. Mohebi is supported by the Barry Fellowship. Dr. Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Kalogeropoulos has received research funding from the National Heart, Lung, and Blood Institute; the American Heart Association; and the Centers for Disease Control and Prevention. Dr. Butler has been a consultant for numerous pharmaceutical companies.

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

A new analysis projects steep increases by 2060 in the prevalence of cardiovascular (CV) risk factors and disease that will disproportionately affect non-White populations who have limited access to health care.

The study by Reza Mohebi, MD, Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues was published in the Journal of the American College of Cardiology.

“Even though several assumptions underlie these projections, the importance of this work cannot be overestimated,” Andreas P. Kalogeropoulos, MD, MPH, PhD, and Javed Butler, MD, MPH, MBA, wrote in an accompanying editorial. “The absolute numbers are staggering.”

From 2025 to 2060, the number of people with any one of four CV risk factors – type 2 diabetes, hypertension, dyslipidemia, and obesity – is projected to increase by 15.4 million, to 34.7 million.

And the number of people with of any one of four CV disease types – ischemic heart disease, heart failure, MI, and stroke – is projected to increase by 3.2 million, to 6.8 million.

Although the model predicts that the prevalence of CV risk factors will gradually decrease among White Americans, the highest prevalence of CV risk factors will be among the White population because of its overall size.

Conversely, the projected prevalence of CV risk factors is expected to increase in Black, Hispanic, Asian, and other race/ethnicity populations.

In parallel, the prevalence of CV disease is projected to decrease in the White population and increase among all other race/ethnicities, particularly in the Black and Hispanic populations.

Courtesy Massachusetts General Hospital

“Our results project a worrisome increase with a particularly ominous increase in risk factors and disease in our most vulnerable patients, including Blacks and Hispanics,” senior author James L. Januzzi Jr., MD, summarized in a video issued by the society.

“The steep rise in CV risk factors and disease reflects the generally higher prevalence in populations projected to increase in the United States, owing to immigration and growth, including Black or Hispanic individuals,” Dr. Januzzi, also from Massachusetts General and Harvard, said in an interview.

“The disproportionate size of the risk is expected in a sense, as minority populations are disproportionately disadvantaged with respect to their health care,” he said. “But whether it is expected or not, the increase in projected prevalence is, nonetheless, concerning and a call to action.”

This study identifies “areas of opportunity for change in the U.S. health care system,” he continued. “Business as usual will result in us encountering a huge number of individuals with CV risk factors and diseases.”

The results from the current analysis assume there will be no modification in health care policies or changes in access to care for at-risk populations, Dr. Mohebi and colleagues noted.

To “stem the rising tide of CV disease in at-risk individuals,” would require strategies such as “emphasis on education regarding CV risk factors, improving access to quality healthcare, and facilitating lower-cost access to effective therapies for treatment of CV risk factors,” according to the researchers.

“Such advances need to be applied in a more equitable way throughout the United States, however,” they cautioned.
 

Census plus NHANES data

The researchers used 2020 U.S. census data and projected growth and 2013-2018 U.S. National Health and Nutrition Survey data to estimate the number of people with CV risk factors and CV disease from 2025 to 2060.

The estimates are based on a growing population and a fixed frequency.

Changing demographic landscape

It is “striking” that the numbers of non-White individuals with CV risk factors is projected to surpass the number of White individuals over time, and the number of non-White individuals with CV disease will be almost as many as White individuals by the year 2060, the editorialists noted.

“From a policy perspective, this means that unless appropriate, targeted action is taken, disparities in the burden of cardiovascular disease are only going to be exacerbated over time,” wrote Dr. Kalogeropoulos, from Stony Brook (N.Y.) University, and Dr. Butler, from Baylor College of Medicine, Dallas.

“On the positive side,” they continued, “the absolute increase in the percent prevalence of cardiovascular risk factors and conditions is projected to lie within a manageable range,” assuming that specific prevention policies are implemented.

“This is an opportunity for professional societies, including the cardiovascular care community, to re-evaluate priorities and strategies, for both training and practice, to best match the growing demands of a changing demographic landscape in the United States,” Dr. Kalogeropoulos and Dr. Butler concluded.

Dr. Mohebi is supported by the Barry Fellowship. Dr. Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Kalogeropoulos has received research funding from the National Heart, Lung, and Blood Institute; the American Heart Association; and the Centers for Disease Control and Prevention. Dr. Butler has been a consultant for numerous pharmaceutical companies.

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

A new analysis projects steep increases by 2060 in the prevalence of cardiovascular (CV) risk factors and disease that will disproportionately affect non-White populations who have limited access to health care.

The study by Reza Mohebi, MD, Massachusetts General Hospital and Harvard Medical School, both in Boston, and colleagues was published in the Journal of the American College of Cardiology.

“Even though several assumptions underlie these projections, the importance of this work cannot be overestimated,” Andreas P. Kalogeropoulos, MD, MPH, PhD, and Javed Butler, MD, MPH, MBA, wrote in an accompanying editorial. “The absolute numbers are staggering.”

From 2025 to 2060, the number of people with any one of four CV risk factors – type 2 diabetes, hypertension, dyslipidemia, and obesity – is projected to increase by 15.4 million, to 34.7 million.

And the number of people with of any one of four CV disease types – ischemic heart disease, heart failure, MI, and stroke – is projected to increase by 3.2 million, to 6.8 million.

Although the model predicts that the prevalence of CV risk factors will gradually decrease among White Americans, the highest prevalence of CV risk factors will be among the White population because of its overall size.

Conversely, the projected prevalence of CV risk factors is expected to increase in Black, Hispanic, Asian, and other race/ethnicity populations.

In parallel, the prevalence of CV disease is projected to decrease in the White population and increase among all other race/ethnicities, particularly in the Black and Hispanic populations.

Courtesy Massachusetts General Hospital

“Our results project a worrisome increase with a particularly ominous increase in risk factors and disease in our most vulnerable patients, including Blacks and Hispanics,” senior author James L. Januzzi Jr., MD, summarized in a video issued by the society.

“The steep rise in CV risk factors and disease reflects the generally higher prevalence in populations projected to increase in the United States, owing to immigration and growth, including Black or Hispanic individuals,” Dr. Januzzi, also from Massachusetts General and Harvard, said in an interview.

“The disproportionate size of the risk is expected in a sense, as minority populations are disproportionately disadvantaged with respect to their health care,” he said. “But whether it is expected or not, the increase in projected prevalence is, nonetheless, concerning and a call to action.”

This study identifies “areas of opportunity for change in the U.S. health care system,” he continued. “Business as usual will result in us encountering a huge number of individuals with CV risk factors and diseases.”

The results from the current analysis assume there will be no modification in health care policies or changes in access to care for at-risk populations, Dr. Mohebi and colleagues noted.

To “stem the rising tide of CV disease in at-risk individuals,” would require strategies such as “emphasis on education regarding CV risk factors, improving access to quality healthcare, and facilitating lower-cost access to effective therapies for treatment of CV risk factors,” according to the researchers.

“Such advances need to be applied in a more equitable way throughout the United States, however,” they cautioned.
 

Census plus NHANES data

The researchers used 2020 U.S. census data and projected growth and 2013-2018 U.S. National Health and Nutrition Survey data to estimate the number of people with CV risk factors and CV disease from 2025 to 2060.

The estimates are based on a growing population and a fixed frequency.

Changing demographic landscape

It is “striking” that the numbers of non-White individuals with CV risk factors is projected to surpass the number of White individuals over time, and the number of non-White individuals with CV disease will be almost as many as White individuals by the year 2060, the editorialists noted.

“From a policy perspective, this means that unless appropriate, targeted action is taken, disparities in the burden of cardiovascular disease are only going to be exacerbated over time,” wrote Dr. Kalogeropoulos, from Stony Brook (N.Y.) University, and Dr. Butler, from Baylor College of Medicine, Dallas.

“On the positive side,” they continued, “the absolute increase in the percent prevalence of cardiovascular risk factors and conditions is projected to lie within a manageable range,” assuming that specific prevention policies are implemented.

“This is an opportunity for professional societies, including the cardiovascular care community, to re-evaluate priorities and strategies, for both training and practice, to best match the growing demands of a changing demographic landscape in the United States,” Dr. Kalogeropoulos and Dr. Butler concluded.

Dr. Mohebi is supported by the Barry Fellowship. Dr. Januzzi is supported by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Abbott Diagnostics, Applied Therapeutics, Innolife, and Novartis; has received consulting income from Abbott Diagnostics, Boehringer Ingelheim, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for AbbVie, Siemens, Takeda, and Vifor. Dr. Kalogeropoulos has received research funding from the National Heart, Lung, and Blood Institute; the American Heart Association; and the Centers for Disease Control and Prevention. Dr. Butler has been a consultant for numerous pharmaceutical companies.

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

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

Pulse oximetry is a vital monitoring tool in the ICU and in pulmonary medicine. Regrettably, re-emerging data show that pulse oximeters do not accurately measure blood oxygen levels in Black patients, presumably due to their skin tone. Patients with darker skin are, therefore, more likely to experience occult hypoxemia (i.e., low arterial oxygen saturation despite a seemingly normal pulse oximetry reading). While inaccuracy of pulse oximeter measurements in patients with darker skin has been recognized for decades, recent studies have highlighted this as an ongoing problem with potentially severe consequences for Black patients and other patients of color.

One recent study found that Black patients had almost three times the likelihood of occult hypoxemia compared with White patients (Sjoding, MW, et al. N Engl J Med. 2020;383[25]:2477-8).

Subsequent studies have confirmed this to be a widespread problem across various clinical settings in hundreds of hospitals (Wong AI, et al. JAMA Netw Open. 2021;4[11]:e2131674; Valbuena VS, et al. Chest. 2022;161[4]:971-8). A recent retrospective cohort study of patients with COVID-19 found that occult hypoxemia in Black and Hispanic patients was associated with delayed eligibility for potentially lifesaving COVID-19 therapies (Fawzy AF, et al. JAMA Intern Med. 2022; published online May 31, 2022).

Now that numerous studies have demonstrated the inaccuracy of pulse oximetry with the potential to cause harm to historically marginalized racial and ethnic groups, must we abandon the use of pulse oximetry? We would argue that pulse oximeters remain valuable tools, but for now, we must adapt our practice until better devices are widely adopted.

First, it is crucial that health professionals are aware that pulse oximeters may underestimate the true extent of hypoxemia for all patients, but particularly for patients with darker skin. Acknowledging this device flaw is essential to avoid harm to our patients.

Second, clinicians must have heightened skepticism for seemingly normal pulse oximetry values when caring for symptomatic patients at risk of occult hypoxemia.

Until better pulse oximeters are widely available, clinicians must consider workarounds aimed at ensuring timely identification of hypoxemia in Black patients and other patients of color.

These patients may need invasive monitoring of arterial oxygenation, including arterial blood gas checks or an arterial catheter. However, invasive monitoring comes at the cost of discomfort to patients and potential complications, such as vessel or nerve damage.

Invasive monitoring of patients at risk for occult hypoxemia is not an equitable or acceptable long-term solution for this problem. As advocates for patients, clinicians and professional organizations should lobby regulatory bodies to ensure pulse oximeters are accurate for all patients.

We must also call on government leaders to move this process forward. For example, in response to efforts by the United Kingdom’s Intensive Care Society, the Health Secretary of the UK, Sajid Javid, has called for a review of pulse oximeters as part of a larger review assessing structural issues in health care that lead to worse outcomes in racial and ethnic minorities (BBC News. https://www.bbc.com/news/uk-59363544. Published online Nov. 21, 2021).

Device companies are largely for-profit corporations with obligations to their shareholders. It seems that existing incentives are insufficient to motivate investment in less biased technology and real-world evaluations of their devices.

We previously called for buyers of pulse oximeters to change the incentives of device companies – that is, for “hospitals to commit to only purchasing pulse oximeters that have been shown to work equally well in patients of colour.” (Hidalgo DC, et al. Lancet Respir Med. 2021;9[4]:E37). And, indeed, we worry that hospitals are putting themselves at medicolegal risk by not raising their purchasing standards. Since it is now widely known that pulse oximeters are inaccurate in certain patients, could there be liability for hospitals that continue to use devices we know to be disproportionately inaccurate by race?

The RNA interference (RNAi) therapeutic patisiran (Onpattro, Alnylam Pharmaceuticals) led to statistically significant improvement in functional capacity and quality of life in adults with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy in the phase 3 APOLLO-B study, according to topline results released Aug. 3.

“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” Pushkal Garg, MD, Alnylam chief medical officer, said in a news release.

The Food and Drug Administration approved patisiran in 2018 for polyneuropathy caused by hereditary ATTR in adults on the basis of results of the APOLLO phase 3 trial, as reported by this news organization.

APOLLO-B enrolled 360 adults with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 centers in 21 countries. Half were randomly allocated to 0.3 mg/kg of patisiran or placebo administered intravenously every 3 weeks for 12 months.

The study met the primary endpoint of a statistically significant improvement from baseline in the 6-minute walk test at 12 months compared with placebo (P = .0162), the company said.

The study also met the first secondary endpoint of a statistically significant improvement from baseline in quality of life compared with placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (P = .0397).

The patisiran and placebo groups had similar frequencies of adverse events (91% and 94%, respectively) and serious adverse events (34% and 35%, respectively).

“ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. These patients have limited treatment options, and disease progression is common. As such, we are encouraged to see the potential of patisiran to improve the functional capacity and quality of life of patients living with this fatal, multisystem disease,” Dr. Garg said in the release.

Full results from APOLLO-B will be presented at a late-breaker session at the 18th International Symposium on Amyloidosis in September in Heidelberg, Germany.

Based on these results, the company plans to file a supplementary new drug application (sNDA) for patisiran for this indication with the FDA later this year, the release noted.

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

The RNA interference (RNAi) therapeutic patisiran (Onpattro, Alnylam Pharmaceuticals) led to statistically significant improvement in functional capacity and quality of life in adults with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy in the phase 3 APOLLO-B study, according to topline results released Aug. 3.

“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” Pushkal Garg, MD, Alnylam chief medical officer, said in a news release.

The Food and Drug Administration approved patisiran in 2018 for polyneuropathy caused by hereditary ATTR in adults on the basis of results of the APOLLO phase 3 trial, as reported by this news organization.

APOLLO-B enrolled 360 adults with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 centers in 21 countries. Half were randomly allocated to 0.3 mg/kg of patisiran or placebo administered intravenously every 3 weeks for 12 months.

The study met the primary endpoint of a statistically significant improvement from baseline in the 6-minute walk test at 12 months compared with placebo (P = .0162), the company said.

The study also met the first secondary endpoint of a statistically significant improvement from baseline in quality of life compared with placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (P = .0397).

The patisiran and placebo groups had similar frequencies of adverse events (91% and 94%, respectively) and serious adverse events (34% and 35%, respectively).

“ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. These patients have limited treatment options, and disease progression is common. As such, we are encouraged to see the potential of patisiran to improve the functional capacity and quality of life of patients living with this fatal, multisystem disease,” Dr. Garg said in the release.

Full results from APOLLO-B will be presented at a late-breaker session at the 18th International Symposium on Amyloidosis in September in Heidelberg, Germany.

Based on these results, the company plans to file a supplementary new drug application (sNDA) for patisiran for this indication with the FDA later this year, the release noted.

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

The RNA interference (RNAi) therapeutic patisiran (Onpattro, Alnylam Pharmaceuticals) led to statistically significant improvement in functional capacity and quality of life in adults with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy in the phase 3 APOLLO-B study, according to topline results released Aug. 3.

“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” Pushkal Garg, MD, Alnylam chief medical officer, said in a news release.

The Food and Drug Administration approved patisiran in 2018 for polyneuropathy caused by hereditary ATTR in adults on the basis of results of the APOLLO phase 3 trial, as reported by this news organization.

APOLLO-B enrolled 360 adults with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 centers in 21 countries. Half were randomly allocated to 0.3 mg/kg of patisiran or placebo administered intravenously every 3 weeks for 12 months.

The study met the primary endpoint of a statistically significant improvement from baseline in the 6-minute walk test at 12 months compared with placebo (P = .0162), the company said.

The study also met the first secondary endpoint of a statistically significant improvement from baseline in quality of life compared with placebo, as measured by the Kansas City Cardiomyopathy Questionnaire (P = .0397).

The patisiran and placebo groups had similar frequencies of adverse events (91% and 94%, respectively) and serious adverse events (34% and 35%, respectively).

“ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. These patients have limited treatment options, and disease progression is common. As such, we are encouraged to see the potential of patisiran to improve the functional capacity and quality of life of patients living with this fatal, multisystem disease,” Dr. Garg said in the release.

Full results from APOLLO-B will be presented at a late-breaker session at the 18th International Symposium on Amyloidosis in September in Heidelberg, Germany.

Based on these results, the company plans to file a supplementary new drug application (sNDA) for patisiran for this indication with the FDA later this year, the release noted.

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

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

Human papillomavirus (HPV) vaccine given around the time women have surgery for precancerous cervical lesions might lead to a reduction in the risk of lesions returning, as well as other HPV-related diseases, but the effects of this remain unclear.

The authors of the new study, published in The BMJ, explained that women who have been treated for high-grade cervical intra-epithelial neoplasia (CIN) have a “lifelong residual high risk of cervical cancer and other malignancies related to HPV infection,” and some research suggests that giving a preventive HPV vaccine alongside treatment for CIN might help to “reduce the risk in these women.”

HPV vaccination is highly effective at preventing the development of precancerous cervical lesions, CIN, and in the U.K., HPV vaccination is offered to girls and boys around the age of 12 or 13.

Eluned Hughes, head of information and engagement at Jo’s Cervical Cancer Trust, said: “Recent evidence has found that cases of cervical cancer have fallen 87% since the introduction of the HPV vaccine program in U.K. schools in 2008.”

“However, women over the age of 27, for whom the vaccine was not available, remain at increased risk of cervical cancer,” she highlighted.
 

Significant risk of bias and scarcity of data

In the study, researchers set out to explore the efficacy of HPV vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment of preinvasive genital disease.

The systematic review and meta-analysis, led by researchers at Imperial College London, screened data from PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov from inception to March 31, 2021.

The researchers analyzed the results of 18 studies – two randomized controlled trials (RCTs), 12 observational studies, and four post-hoc analyses of RCTs.

The authors said that the two RCTs were classified as low risk of bias, while in the observational studies and post-hoc analyses, risk of bias was moderate for seven, serious for seven, and critical for two. Average length of follow-up was 36 months.

There was a reduction of 57% in the risk of recurrence of high-grade pre-invasive disease (CIN2+) in individuals who were vaccinated, compared with those who were not vaccinated. “The effect estimate was “even more pronounced” – a relative 74% reduction – when the risk of recurrence of CIN2+ was assessed for disease related to the two high-risk HPV types – HPV16 and HPV18,” explained the authors.

However, the researchers noted that these effects are unclear because of the “scarcity of data” and the “moderate to high overall risk of bias” of the available studies.
 

Quality of evidence inconclusive – more trials needed

With regards to CIN3, the risk of recurrence of was also reduced in patients who were vaccinated, but there was a high level of uncertainty about the quality of this evidence, cautioned the authors.

Evidence was also lacking on the benefit of HPV vaccination for recurrence of vulvar, vaginal, and anal lesions, as well as genital warts.

Analysis of the post-hoc studies from randomized controlled trial data with historic vaccination at randomization before the development of the disease reported inconsistent results, the authors said.

Several study limitations were acknowledged by the authors, including that most of the studies were observational, of low to moderate quality, and with relatively short follow-up times, which they pointed out prevented assessment of long-term effects. In addition, the average age of participants was not provided in most studies, and factors such as smoking – associated with a higher risk of recurrence – were not controlled for in many studies.

“HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision,” they concluded. However, they cautioned that “quality of evidence indicated that the data were inconclusive.”

“Large, appropriately powered, randomized controlled trials are required to establish the effectiveness of adjuvant HPV vaccination at the time of local surgical treatment of CIN,” they recommended.

“Given that the incidence of recurrence of high-grade disease is low in quality assured national screening programs, such as in the United Kingdom, absolute risks and a cost effectiveness analysis would be important in determining the implementation strategy of HPV vaccination after treatment,” the authors said.

Ms. Hughes said that the charity was pleased to see emerging research into the value of using the HPV vaccine to prevent the recurrence of cervical cell changes. She said that the charity looks forward to seeing “further large-scale studies into the effectiveness of this method.”

In the meantime, the charity encourages all women and other people with a cervix to attend their cervical screening and for young people to have the HPV vaccination when invited, as “these are the best tools we currently have to prevent cervical cancer,” she said.

A version of this article first appeared on Medscape UK.

Human papillomavirus (HPV) vaccine given around the time women have surgery for precancerous cervical lesions might lead to a reduction in the risk of lesions returning, as well as other HPV-related diseases, but the effects of this remain unclear.

The authors of the new study, published in The BMJ, explained that women who have been treated for high-grade cervical intra-epithelial neoplasia (CIN) have a “lifelong residual high risk of cervical cancer and other malignancies related to HPV infection,” and some research suggests that giving a preventive HPV vaccine alongside treatment for CIN might help to “reduce the risk in these women.”

HPV vaccination is highly effective at preventing the development of precancerous cervical lesions, CIN, and in the U.K., HPV vaccination is offered to girls and boys around the age of 12 or 13.

Eluned Hughes, head of information and engagement at Jo’s Cervical Cancer Trust, said: “Recent evidence has found that cases of cervical cancer have fallen 87% since the introduction of the HPV vaccine program in U.K. schools in 2008.”

“However, women over the age of 27, for whom the vaccine was not available, remain at increased risk of cervical cancer,” she highlighted.
 

Significant risk of bias and scarcity of data

In the study, researchers set out to explore the efficacy of HPV vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment of preinvasive genital disease.

The systematic review and meta-analysis, led by researchers at Imperial College London, screened data from PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov from inception to March 31, 2021.

The researchers analyzed the results of 18 studies – two randomized controlled trials (RCTs), 12 observational studies, and four post-hoc analyses of RCTs.

The authors said that the two RCTs were classified as low risk of bias, while in the observational studies and post-hoc analyses, risk of bias was moderate for seven, serious for seven, and critical for two. Average length of follow-up was 36 months.

There was a reduction of 57% in the risk of recurrence of high-grade pre-invasive disease (CIN2+) in individuals who were vaccinated, compared with those who were not vaccinated. “The effect estimate was “even more pronounced” – a relative 74% reduction – when the risk of recurrence of CIN2+ was assessed for disease related to the two high-risk HPV types – HPV16 and HPV18,” explained the authors.

However, the researchers noted that these effects are unclear because of the “scarcity of data” and the “moderate to high overall risk of bias” of the available studies.
 

Quality of evidence inconclusive – more trials needed

With regards to CIN3, the risk of recurrence of was also reduced in patients who were vaccinated, but there was a high level of uncertainty about the quality of this evidence, cautioned the authors.

Evidence was also lacking on the benefit of HPV vaccination for recurrence of vulvar, vaginal, and anal lesions, as well as genital warts.

Analysis of the post-hoc studies from randomized controlled trial data with historic vaccination at randomization before the development of the disease reported inconsistent results, the authors said.

Several study limitations were acknowledged by the authors, including that most of the studies were observational, of low to moderate quality, and with relatively short follow-up times, which they pointed out prevented assessment of long-term effects. In addition, the average age of participants was not provided in most studies, and factors such as smoking – associated with a higher risk of recurrence – were not controlled for in many studies.

“HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision,” they concluded. However, they cautioned that “quality of evidence indicated that the data were inconclusive.”

“Large, appropriately powered, randomized controlled trials are required to establish the effectiveness of adjuvant HPV vaccination at the time of local surgical treatment of CIN,” they recommended.

“Given that the incidence of recurrence of high-grade disease is low in quality assured national screening programs, such as in the United Kingdom, absolute risks and a cost effectiveness analysis would be important in determining the implementation strategy of HPV vaccination after treatment,” the authors said.

Ms. Hughes said that the charity was pleased to see emerging research into the value of using the HPV vaccine to prevent the recurrence of cervical cell changes. She said that the charity looks forward to seeing “further large-scale studies into the effectiveness of this method.”

In the meantime, the charity encourages all women and other people with a cervix to attend their cervical screening and for young people to have the HPV vaccination when invited, as “these are the best tools we currently have to prevent cervical cancer,” she said.

A version of this article first appeared on Medscape UK.

Human papillomavirus (HPV) vaccine given around the time women have surgery for precancerous cervical lesions might lead to a reduction in the risk of lesions returning, as well as other HPV-related diseases, but the effects of this remain unclear.

The authors of the new study, published in The BMJ, explained that women who have been treated for high-grade cervical intra-epithelial neoplasia (CIN) have a “lifelong residual high risk of cervical cancer and other malignancies related to HPV infection,” and some research suggests that giving a preventive HPV vaccine alongside treatment for CIN might help to “reduce the risk in these women.”

HPV vaccination is highly effective at preventing the development of precancerous cervical lesions, CIN, and in the U.K., HPV vaccination is offered to girls and boys around the age of 12 or 13.

Eluned Hughes, head of information and engagement at Jo’s Cervical Cancer Trust, said: “Recent evidence has found that cases of cervical cancer have fallen 87% since the introduction of the HPV vaccine program in U.K. schools in 2008.”

“However, women over the age of 27, for whom the vaccine was not available, remain at increased risk of cervical cancer,” she highlighted.
 

Significant risk of bias and scarcity of data

In the study, researchers set out to explore the efficacy of HPV vaccination on the risk of HPV infection and recurrent diseases related to HPV infection in individuals undergoing local surgical treatment of preinvasive genital disease.

The systematic review and meta-analysis, led by researchers at Imperial College London, screened data from PubMed (Medline), Scopus, Cochrane, Web of Science, and ClinicalTrials.gov from inception to March 31, 2021.

The researchers analyzed the results of 18 studies – two randomized controlled trials (RCTs), 12 observational studies, and four post-hoc analyses of RCTs.

The authors said that the two RCTs were classified as low risk of bias, while in the observational studies and post-hoc analyses, risk of bias was moderate for seven, serious for seven, and critical for two. Average length of follow-up was 36 months.

There was a reduction of 57% in the risk of recurrence of high-grade pre-invasive disease (CIN2+) in individuals who were vaccinated, compared with those who were not vaccinated. “The effect estimate was “even more pronounced” – a relative 74% reduction – when the risk of recurrence of CIN2+ was assessed for disease related to the two high-risk HPV types – HPV16 and HPV18,” explained the authors.

However, the researchers noted that these effects are unclear because of the “scarcity of data” and the “moderate to high overall risk of bias” of the available studies.
 

Quality of evidence inconclusive – more trials needed

With regards to CIN3, the risk of recurrence of was also reduced in patients who were vaccinated, but there was a high level of uncertainty about the quality of this evidence, cautioned the authors.

Evidence was also lacking on the benefit of HPV vaccination for recurrence of vulvar, vaginal, and anal lesions, as well as genital warts.

Analysis of the post-hoc studies from randomized controlled trial data with historic vaccination at randomization before the development of the disease reported inconsistent results, the authors said.

Several study limitations were acknowledged by the authors, including that most of the studies were observational, of low to moderate quality, and with relatively short follow-up times, which they pointed out prevented assessment of long-term effects. In addition, the average age of participants was not provided in most studies, and factors such as smoking – associated with a higher risk of recurrence – were not controlled for in many studies.

“HPV vaccination might reduce the risk of recurrence of CIN, in particular when related to HPV16 or HPV18, in women treated with local excision,” they concluded. However, they cautioned that “quality of evidence indicated that the data were inconclusive.”

“Large, appropriately powered, randomized controlled trials are required to establish the effectiveness of adjuvant HPV vaccination at the time of local surgical treatment of CIN,” they recommended.

“Given that the incidence of recurrence of high-grade disease is low in quality assured national screening programs, such as in the United Kingdom, absolute risks and a cost effectiveness analysis would be important in determining the implementation strategy of HPV vaccination after treatment,” the authors said.

Ms. Hughes said that the charity was pleased to see emerging research into the value of using the HPV vaccine to prevent the recurrence of cervical cell changes. She said that the charity looks forward to seeing “further large-scale studies into the effectiveness of this method.”

In the meantime, the charity encourages all women and other people with a cervix to attend their cervical screening and for young people to have the HPV vaccination when invited, as “these are the best tools we currently have to prevent cervical cancer,” she said.

A version of this article first appeared on Medscape UK.

Regular exercise, regardless of intensity level, appears to slow cognitive decline in sedentary older adults with mild cognitive impariment (MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.

“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.

The topline results were presented at the 2022 Alzheimer’s Association International Conference.
 

No decline

The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).

Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.

Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.

During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.

Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.

“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
 

Supported exercise is ‘crucial’

To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.

In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.

Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.

A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.

“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.

“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.

In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
 

Important study

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.

“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.

“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.

Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”

The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.

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

Regular exercise, regardless of intensity level, appears to slow cognitive decline in sedentary older adults with mild cognitive impariment (MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.

“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.

The topline results were presented at the 2022 Alzheimer’s Association International Conference.
 

No decline

The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).

Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.

Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.

During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.

Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.

“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
 

Supported exercise is ‘crucial’

To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.

In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.

Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.

A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.

“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.

“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.

In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
 

Important study

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.

“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.

“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.

Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”

The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.

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

Regular exercise, regardless of intensity level, appears to slow cognitive decline in sedentary older adults with mild cognitive impariment (MCI), new research from the largest study of its kind suggests. Topline results from the EXERT trial showed patients with MCI who participated regularly in either aerobic exercise or stretching/balance/range-of-motion exercises maintained stable global cognitive function over 12 months of follow-up – with no differences between the two types of exercise.

“We’re excited about these findings, because these types of exercises that we’re seeing can protect against cognitive decline are accessible to everyone and therefore scalable to the public,” study investigator Laura Baker, PhD, Wake Forest University School of Medicine, Winston-Salem, N.C., said at a press briefing.

The topline results were presented at the 2022 Alzheimer’s Association International Conference.
 

No decline

The 18-month EXERT trial was designed to be the definitive study to answer the question about whether exercise can slow cognitive decline in older adults with amnestic MCI, Dr. Baker reported. Investigators enrolled 296 sedentary men and women with MCI (mean age, about 75 years). All were randomly allocated to either an aerobic exercise group (maintaining a heart rate at about 70%-85%) or a stretching and balance group (maintaining heart rate less than 35%).

Both groups exercised four times per week for about 30-40 minutes. In the first 12 months they were supervised by a trainer at the YMCA and then they exercised independently for the final 6 months.

Participants were assessed at baseline and every 6 months. The primary endpoint was change from baseline on the ADAS-Cog-Exec, a validated measure of global cognitive function, at the end of the 12 months of supervised exercise.

During the first 12 months, participants completed over 31,000 sessions of exercise, which is “quite impressive,” Dr. Baker said.

Over the first 12 months, neither the aerobic group nor the stretch/balance group showed a decline on the ADAS-Cog-Exec.

“We saw no group differences, and importantly, no decline after 12 months,” Dr. Baker reported.
 

Supported exercise is ‘crucial’

To help “make sense” of these findings, Dr. Baker noted that 12-month changes in the ADAS-Cog-Exec for the EXERT intervention groups were also compared with a “usual care” cohort of adults matched for age, sex, education, baseline cognitive status, and APOE4 genotype.

In this “apples-to-apples” comparison, the usual care cohort showed the expected decline or worsening of cognitive function over 12 months on the ADAS-Cog-Exec, but the EXERT exercise groups did not.

Dr. Baker noted that both exercise groups received equal amounts of weekly socialization, which may have contributed to the apparent protective effects on the brain.

A greater volume of exercise in EXERT, compared with other trials, may also be a factor. Each individual participant in EXERT completed more than 100 hours of exercise.

“The take-home message is that an increased amount of either low-intensity or high-intensity exercise for 120-150 minutes per week for 12 months may slow cognitive decline in sedentary older adults with MCI,” Dr. Baker said.

“What’s critical is that this regular exercise must be supported in these older [patients] with MCI. It must be supervised. There has to be some social component,” she added.

In her view, 120 minutes of regular supported exercise for sedentary individuals with MCI “needs to be part of the recommendation for risk reduction.”
 

Important study

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that several studies over the years have suggested that different types of exercise can have benefits on the brain.

“What’s important about this study is that it’s in a population of people that have MCI and are already experiencing memory changes,” Dr. Snyder said.

“The results suggest that engaging in both of these types of exercise may be beneficial for our brain. And given that this is the largest study of its kind in a population of people with MCI, it suggests it’s ‘never too late’ to start exercising,” she added.

Dr. Snyder noted the importance of continuing this work and to continue following these individuals “over time as well.”

The study was funded by the National Institutes of Health, National Institute on Aging. Dr. Baker and Dr. Snyder have disclosed no relevant financial relationships.

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

Consistently earning a low salary in midlife is associated with increased memory decline in older age, new research suggests. In a new analysis of more than 3,000 participants in the Health and Retirement Study, those who sustained low wages in midlife showed significantly faster memory decline than their peers who never earned low wages.

The findings could have implications for future public policy and research initiatives, the investigators noted.

“Our findings, which suggest a pattern of sustained low-wage earning is harmful for cognitive health, [are] broadly applicable to researchers across numerous health disciplines,” said co-investigator Katrina Kezios, PhD, postdoctoral researcher, department of epidemiology, Mailman School of Public Health, Columbia University, New York.

The findings were presented at the 2022 Alzheimer’s Association International Conference.
 

Growing number of low-wage workers

Low-wage workers make up a growing share of the U.S. labor market. Yet little research has examined the long-term relationship between earning low wages and memory decline.

The current investigators assessed 1992-2016 data from the Health and Retirement Study, a longitudinal survey of nationally representative samples of Americans aged 50 years and older. Study participants are interviewed every 2 years and provide, among other things, information on work-related factors, including hourly wages.

Memory function was measured at each visit from 2004 to 2016 using a memory composite score. The score included immediate and delayed word recall memory assessments. For those who became too impaired to complete cognitive assessment, memory tests by proxy informants were utilized.

On average, participants completed 4.8 memory assessments over the course of the study.

Researchers defined “low wage” as an hourly wage lower than two-thirds of the federal median wage for the corresponding year. They categorized low-wage exposure history as “never” or “intermittent” or “sustained” on the basis of wages earned from 1992 to 2004.

The current analysis included 3,803 participants, 1,913 of whom were men. All participants were born from 1936 to 1941. In 2004, the average age was 65 years, and the mean memory score was 1.15 standard units.

The investigators adjusted for factors that could confound the relationship between wages and cognition, including the participant’s education, parental education, household wealth, and marital status. Later, whether the participants’ occupation type was of low skill or not was also included.
 

Cognitive harm

The confounder-adjusted annual rate of memory decline among workers who never earned low wages was –0.12 standard units (95% confidence interval, –0.14 to –0.10).

Compared with these workers, memory decline was significantly faster among participants with sustained low wage–earning during midlife (beta for interaction between time and exposure group, –0.012; 95% CI, –0.02 to 0.01), corresponding to an annual rate of –0.13 standard units.

Put another way, the cognitive aging experienced by workers earning low wages over a 10-year period was equivalent to what workers who never earned low wages would experience over 11 years.

Although similar associations were found for men and women, it was stronger in magnitude for men – a finding Dr. Kezios said was somewhat surprising. She noted that women are commonly more at risk for dementia than men.

However, she advises caution in interpreting this finding, as there were so few men in the sustained low-wage group. “Women disproportionately make up the group of workers earning low wages,” she said.

The negative low coefficient found for those who persistently earned low wages was also observed for those who intermittently earned low wages, but this was not statistically significant.

“We can speculate or hypothesize the cumulative effect of earning low wages at each exposure interval produces more cognitive harm than maybe earning low wages at some time points over that exposure period,” said Dr. Kezios.

A sensitivity analysis that examined wage earning at the same ages but in two different birth cohorts showed similar results for the two groups. When researchers removed self-employed workers from the study sample, the same association between sustained low wages and memory decline was found.

“Our findings held up, which gave us a little more reassurance that what we were seeing is at least signaling there might be something there,” said Dr. Kezios.

She described the study as a “first pass” for documenting the harmful cognitive effects of consistently earning low wages.

It would be interesting, she said, to now determine whether there’s a “dose effect” for having a low salary. However, other studies with different designs would be needed to determine at what income level cognitive health starts to be protected and the impact of raising the minimum wage, she added.
 

Unique study

Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said the study was unique. “I don’t think we have seen anything like this before,” said Dr. Snyder.

The study, which links sustained low-wage earning in midlife to later memory decline, “is looking beyond some of the other measures we’ve seen when we looked at socioeconomic status,” she noted.

The results “beg the question” of whether people who earn low wages have less access to health care, she added.

“We should think about how to ensure access and equity around health care and around potential ways that may address components of risk individuals have during their life course,” Dr. Snyder said.

She noted that the study provides a “start” at considering potential policies to address the impact of sustained low wages on overall health, particularly cognitive health, throughout life.

The study had no outside funding. Dr. Kezios has reported no relevant financial relationships.

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

Consistently earning a low salary in midlife is associated with increased memory decline in older age, new research suggests. In a new analysis of more than 3,000 participants in the Health and Retirement Study, those who sustained low wages in midlife showed significantly faster memory decline than their peers who never earned low wages.

The findings could have implications for future public policy and research initiatives, the investigators noted.

“Our findings, which suggest a pattern of sustained low-wage earning is harmful for cognitive health, [are] broadly applicable to researchers across numerous health disciplines,” said co-investigator Katrina Kezios, PhD, postdoctoral researcher, department of epidemiology, Mailman School of Public Health, Columbia University, New York.

The findings were presented at the 2022 Alzheimer’s Association International Conference.
 

Growing number of low-wage workers

Low-wage workers make up a growing share of the U.S. labor market. Yet little research has examined the long-term relationship between earning low wages and memory decline.

The current investigators assessed 1992-2016 data from the Health and Retirement Study, a longitudinal survey of nationally representative samples of Americans aged 50 years and older. Study participants are interviewed every 2 years and provide, among other things, information on work-related factors, including hourly wages.

Memory function was measured at each visit from 2004 to 2016 using a memory composite score. The score included immediate and delayed word recall memory assessments. For those who became too impaired to complete cognitive assessment, memory tests by proxy informants were utilized.

On average, participants completed 4.8 memory assessments over the course of the study.

Researchers defined “low wage” as an hourly wage lower than two-thirds of the federal median wage for the corresponding year. They categorized low-wage exposure history as “never” or “intermittent” or “sustained” on the basis of wages earned from 1992 to 2004.

The current analysis included 3,803 participants, 1,913 of whom were men. All participants were born from 1936 to 1941. In 2004, the average age was 65 years, and the mean memory score was 1.15 standard units.

The investigators adjusted for factors that could confound the relationship between wages and cognition, including the participant’s education, parental education, household wealth, and marital status. Later, whether the participants’ occupation type was of low skill or not was also included.
 

Cognitive harm

The confounder-adjusted annual rate of memory decline among workers who never earned low wages was –0.12 standard units (95% confidence interval, –0.14 to –0.10).

Compared with these workers, memory decline was significantly faster among participants with sustained low wage–earning during midlife (beta for interaction between time and exposure group, –0.012; 95% CI, –0.02 to 0.01), corresponding to an annual rate of –0.13 standard units.

Put another way, the cognitive aging experienced by workers earning low wages over a 10-year period was equivalent to what workers who never earned low wages would experience over 11 years.

Although similar associations were found for men and women, it was stronger in magnitude for men – a finding Dr. Kezios said was somewhat surprising. She noted that women are commonly more at risk for dementia than men.

However, she advises caution in interpreting this finding, as there were so few men in the sustained low-wage group. “Women disproportionately make up the group of workers earning low wages,” she said.

The negative low coefficient found for those who persistently earned low wages was also observed for those who intermittently earned low wages, but this was not statistically significant.

“We can speculate or hypothesize the cumulative effect of earning low wages at each exposure interval produces more cognitive harm than maybe earning low wages at some time points over that exposure period,” said Dr. Kezios.

A sensitivity analysis that examined wage earning at the same ages but in two different birth cohorts showed similar results for the two groups. When researchers removed self-employed workers from the study sample, the same association between sustained low wages and memory decline was found.

“Our findings held up, which gave us a little more reassurance that what we were seeing is at least signaling there might be something there,” said Dr. Kezios.

She described the study as a “first pass” for documenting the harmful cognitive effects of consistently earning low wages.

It would be interesting, she said, to now determine whether there’s a “dose effect” for having a low salary. However, other studies with different designs would be needed to determine at what income level cognitive health starts to be protected and the impact of raising the minimum wage, she added.
 

Unique study

Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said the study was unique. “I don’t think we have seen anything like this before,” said Dr. Snyder.

The study, which links sustained low-wage earning in midlife to later memory decline, “is looking beyond some of the other measures we’ve seen when we looked at socioeconomic status,” she noted.

The results “beg the question” of whether people who earn low wages have less access to health care, she added.

“We should think about how to ensure access and equity around health care and around potential ways that may address components of risk individuals have during their life course,” Dr. Snyder said.

She noted that the study provides a “start” at considering potential policies to address the impact of sustained low wages on overall health, particularly cognitive health, throughout life.

The study had no outside funding. Dr. Kezios has reported no relevant financial relationships.

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

Consistently earning a low salary in midlife is associated with increased memory decline in older age, new research suggests. In a new analysis of more than 3,000 participants in the Health and Retirement Study, those who sustained low wages in midlife showed significantly faster memory decline than their peers who never earned low wages.

The findings could have implications for future public policy and research initiatives, the investigators noted.

“Our findings, which suggest a pattern of sustained low-wage earning is harmful for cognitive health, [are] broadly applicable to researchers across numerous health disciplines,” said co-investigator Katrina Kezios, PhD, postdoctoral researcher, department of epidemiology, Mailman School of Public Health, Columbia University, New York.

The findings were presented at the 2022 Alzheimer’s Association International Conference.
 

Growing number of low-wage workers

Low-wage workers make up a growing share of the U.S. labor market. Yet little research has examined the long-term relationship between earning low wages and memory decline.

The current investigators assessed 1992-2016 data from the Health and Retirement Study, a longitudinal survey of nationally representative samples of Americans aged 50 years and older. Study participants are interviewed every 2 years and provide, among other things, information on work-related factors, including hourly wages.

Memory function was measured at each visit from 2004 to 2016 using a memory composite score. The score included immediate and delayed word recall memory assessments. For those who became too impaired to complete cognitive assessment, memory tests by proxy informants were utilized.

On average, participants completed 4.8 memory assessments over the course of the study.

Researchers defined “low wage” as an hourly wage lower than two-thirds of the federal median wage for the corresponding year. They categorized low-wage exposure history as “never” or “intermittent” or “sustained” on the basis of wages earned from 1992 to 2004.

The current analysis included 3,803 participants, 1,913 of whom were men. All participants were born from 1936 to 1941. In 2004, the average age was 65 years, and the mean memory score was 1.15 standard units.

The investigators adjusted for factors that could confound the relationship between wages and cognition, including the participant’s education, parental education, household wealth, and marital status. Later, whether the participants’ occupation type was of low skill or not was also included.
 

Cognitive harm

The confounder-adjusted annual rate of memory decline among workers who never earned low wages was –0.12 standard units (95% confidence interval, –0.14 to –0.10).

Compared with these workers, memory decline was significantly faster among participants with sustained low wage–earning during midlife (beta for interaction between time and exposure group, –0.012; 95% CI, –0.02 to 0.01), corresponding to an annual rate of –0.13 standard units.

Put another way, the cognitive aging experienced by workers earning low wages over a 10-year period was equivalent to what workers who never earned low wages would experience over 11 years.

Although similar associations were found for men and women, it was stronger in magnitude for men – a finding Dr. Kezios said was somewhat surprising. She noted that women are commonly more at risk for dementia than men.

However, she advises caution in interpreting this finding, as there were so few men in the sustained low-wage group. “Women disproportionately make up the group of workers earning low wages,” she said.

The negative low coefficient found for those who persistently earned low wages was also observed for those who intermittently earned low wages, but this was not statistically significant.

“We can speculate or hypothesize the cumulative effect of earning low wages at each exposure interval produces more cognitive harm than maybe earning low wages at some time points over that exposure period,” said Dr. Kezios.

A sensitivity analysis that examined wage earning at the same ages but in two different birth cohorts showed similar results for the two groups. When researchers removed self-employed workers from the study sample, the same association between sustained low wages and memory decline was found.

“Our findings held up, which gave us a little more reassurance that what we were seeing is at least signaling there might be something there,” said Dr. Kezios.

She described the study as a “first pass” for documenting the harmful cognitive effects of consistently earning low wages.

It would be interesting, she said, to now determine whether there’s a “dose effect” for having a low salary. However, other studies with different designs would be needed to determine at what income level cognitive health starts to be protected and the impact of raising the minimum wage, she added.
 

Unique study

Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said the study was unique. “I don’t think we have seen anything like this before,” said Dr. Snyder.

The study, which links sustained low-wage earning in midlife to later memory decline, “is looking beyond some of the other measures we’ve seen when we looked at socioeconomic status,” she noted.

The results “beg the question” of whether people who earn low wages have less access to health care, she added.

“We should think about how to ensure access and equity around health care and around potential ways that may address components of risk individuals have during their life course,” Dr. Snyder said.

She noted that the study provides a “start” at considering potential policies to address the impact of sustained low wages on overall health, particularly cognitive health, throughout life.

The study had no outside funding. Dr. Kezios has reported no relevant financial relationships.

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