Cardiology News

A recent poll found 35% of employers plan to implement some sort of COVID-19 vaccine mandate for workers, despite a recent U.S. Supreme Court ruling that blocked the Biden administration’s vaccine-or-test rule for big businesses.

But the poll by Gartner Inc. showed no consensus among employers. About 4% of polled executives said they’re dropping their vaccine mandate, 29% are in a wait-and-see position, and 12% are less likely to impose a mandate now, Bloomberg reported.

Executives were divided on how a vaccine mandate would affect absenteeism and employee morale. Almost 40% of polled employers said they thought a mandate would attract workers, but about 25% said it would do the opposite, Bloomberg said.

“What is more attractive -- to have a mandate or not?” Brian Kropp, PhD, Gartner’s chief of human resources research, said in an interview with Bloomberg. “Most are not exactly sure what to do.”

Big companies have reacted differently since the court’s ruling.

Starbucks announced it was dropping its vaccine-or-test rule for the company’s approximately 228,000 employees. General Electric dropped its mandate after the ruling, but Honeywell International Inc. announced it was staying with its vaccination policy, Bloomberg said.

The Supreme Court ruled Jan. 13 against the Biden administration’s mandate for businesses. The Occupational Safety and Health Administration had proposed that every company with more than 100 employees would be required to ensure workers were either vaccinated or tested weekly for COVID-19.

State governments and business groups immediately appealed, and the court ruled 6-3 against the mandate. The Biden administration officially dropped its rule on Wednesday.

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

A recent poll found 35% of employers plan to implement some sort of COVID-19 vaccine mandate for workers, despite a recent U.S. Supreme Court ruling that blocked the Biden administration’s vaccine-or-test rule for big businesses.

But the poll by Gartner Inc. showed no consensus among employers. About 4% of polled executives said they’re dropping their vaccine mandate, 29% are in a wait-and-see position, and 12% are less likely to impose a mandate now, Bloomberg reported.

Executives were divided on how a vaccine mandate would affect absenteeism and employee morale. Almost 40% of polled employers said they thought a mandate would attract workers, but about 25% said it would do the opposite, Bloomberg said.

“What is more attractive -- to have a mandate or not?” Brian Kropp, PhD, Gartner’s chief of human resources research, said in an interview with Bloomberg. “Most are not exactly sure what to do.”

Big companies have reacted differently since the court’s ruling.

Starbucks announced it was dropping its vaccine-or-test rule for the company’s approximately 228,000 employees. General Electric dropped its mandate after the ruling, but Honeywell International Inc. announced it was staying with its vaccination policy, Bloomberg said.

The Supreme Court ruled Jan. 13 against the Biden administration’s mandate for businesses. The Occupational Safety and Health Administration had proposed that every company with more than 100 employees would be required to ensure workers were either vaccinated or tested weekly for COVID-19.

State governments and business groups immediately appealed, and the court ruled 6-3 against the mandate. The Biden administration officially dropped its rule on Wednesday.

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

A recent poll found 35% of employers plan to implement some sort of COVID-19 vaccine mandate for workers, despite a recent U.S. Supreme Court ruling that blocked the Biden administration’s vaccine-or-test rule for big businesses.

But the poll by Gartner Inc. showed no consensus among employers. About 4% of polled executives said they’re dropping their vaccine mandate, 29% are in a wait-and-see position, and 12% are less likely to impose a mandate now, Bloomberg reported.

Executives were divided on how a vaccine mandate would affect absenteeism and employee morale. Almost 40% of polled employers said they thought a mandate would attract workers, but about 25% said it would do the opposite, Bloomberg said.

“What is more attractive -- to have a mandate or not?” Brian Kropp, PhD, Gartner’s chief of human resources research, said in an interview with Bloomberg. “Most are not exactly sure what to do.”

Big companies have reacted differently since the court’s ruling.

Starbucks announced it was dropping its vaccine-or-test rule for the company’s approximately 228,000 employees. General Electric dropped its mandate after the ruling, but Honeywell International Inc. announced it was staying with its vaccination policy, Bloomberg said.

The Supreme Court ruled Jan. 13 against the Biden administration’s mandate for businesses. The Occupational Safety and Health Administration had proposed that every company with more than 100 employees would be required to ensure workers were either vaccinated or tested weekly for COVID-19.

State governments and business groups immediately appealed, and the court ruled 6-3 against the mandate. The Biden administration officially dropped its rule on Wednesday.

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

More than 1 in 10 Americans have diabetes and over a third have prediabetes, according to updated statistics from the Centers for Disease Control and Prevention.

The National Diabetes Statistics Report includes data for 2017-2020 from several nationally representative sources on prevalence and incidence of diabetes and prediabetes, risk factors for complications, acute and long-term complications, and costs.

According to the new report, published on Jan. 25, a total of 37.3 million people in the United States have diabetes, or about 11.3% of the population. Of those, 28.7 million are diagnosed (including 28.5 million adults), while 8.5 million, or 23% of those with diabetes, are undiagnosed.

Another 96 million adults have prediabetes, comprising 38.0% of the adult U.S. population, of whom only 19% are aware of their prediabetes status.

In a statement, the American Diabetes Association said the new CDC data “show an alarming increase of diabetes in our nation among adults,” while the high number with prediabetes who don’t know that they have it “is fueling the diabetes epidemic.”

Regarding the total estimated 1.84 million with type 1 diabetes, the advocacy organization JDRF said in a statement: “These data and additional statistical research reinforces the urgency to accelerate life-changing breakthroughs to cure, prevent, and treat [type 1 diabetes] and its complications.”

Overall, the ADA said, “the National Diabetes Statistics Report reaffirms why the ADA is dedicated to innovative research to find a cure for diabetes once and for all.”
 

Notable increases since 2019

These new data represent notable increases since the CDC’s 2019 Report Card, which gave the U.S. population with diabetes in 2018 as 34.2 million, or 10.5% of the population, including 7.3 million undiagnosed. The prediabetes prevalence that year was 88 million.

Among children and adolescents younger than 20 years, 283,000, or 35 per 10,000 U.S. youths, had diagnosed diabetes in 2019. Of those, 244,000 had type 1 diabetes. Another 1.6 million adults aged 20 and older also reported having type 1 diabetes, comprising 5.7% of U.S. adults with diagnosed diabetes.

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

More than 1 in 10 Americans have diabetes and over a third have prediabetes, according to updated statistics from the Centers for Disease Control and Prevention.

The National Diabetes Statistics Report includes data for 2017-2020 from several nationally representative sources on prevalence and incidence of diabetes and prediabetes, risk factors for complications, acute and long-term complications, and costs.

According to the new report, published on Jan. 25, a total of 37.3 million people in the United States have diabetes, or about 11.3% of the population. Of those, 28.7 million are diagnosed (including 28.5 million adults), while 8.5 million, or 23% of those with diabetes, are undiagnosed.

Another 96 million adults have prediabetes, comprising 38.0% of the adult U.S. population, of whom only 19% are aware of their prediabetes status.

In a statement, the American Diabetes Association said the new CDC data “show an alarming increase of diabetes in our nation among adults,” while the high number with prediabetes who don’t know that they have it “is fueling the diabetes epidemic.”

Regarding the total estimated 1.84 million with type 1 diabetes, the advocacy organization JDRF said in a statement: “These data and additional statistical research reinforces the urgency to accelerate life-changing breakthroughs to cure, prevent, and treat [type 1 diabetes] and its complications.”

Overall, the ADA said, “the National Diabetes Statistics Report reaffirms why the ADA is dedicated to innovative research to find a cure for diabetes once and for all.”
 

Notable increases since 2019

These new data represent notable increases since the CDC’s 2019 Report Card, which gave the U.S. population with diabetes in 2018 as 34.2 million, or 10.5% of the population, including 7.3 million undiagnosed. The prediabetes prevalence that year was 88 million.

Among children and adolescents younger than 20 years, 283,000, or 35 per 10,000 U.S. youths, had diagnosed diabetes in 2019. Of those, 244,000 had type 1 diabetes. Another 1.6 million adults aged 20 and older also reported having type 1 diabetes, comprising 5.7% of U.S. adults with diagnosed diabetes.

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

More than 1 in 10 Americans have diabetes and over a third have prediabetes, according to updated statistics from the Centers for Disease Control and Prevention.

The National Diabetes Statistics Report includes data for 2017-2020 from several nationally representative sources on prevalence and incidence of diabetes and prediabetes, risk factors for complications, acute and long-term complications, and costs.

According to the new report, published on Jan. 25, a total of 37.3 million people in the United States have diabetes, or about 11.3% of the population. Of those, 28.7 million are diagnosed (including 28.5 million adults), while 8.5 million, or 23% of those with diabetes, are undiagnosed.

Another 96 million adults have prediabetes, comprising 38.0% of the adult U.S. population, of whom only 19% are aware of their prediabetes status.

In a statement, the American Diabetes Association said the new CDC data “show an alarming increase of diabetes in our nation among adults,” while the high number with prediabetes who don’t know that they have it “is fueling the diabetes epidemic.”

Regarding the total estimated 1.84 million with type 1 diabetes, the advocacy organization JDRF said in a statement: “These data and additional statistical research reinforces the urgency to accelerate life-changing breakthroughs to cure, prevent, and treat [type 1 diabetes] and its complications.”

Overall, the ADA said, “the National Diabetes Statistics Report reaffirms why the ADA is dedicated to innovative research to find a cure for diabetes once and for all.”
 

Notable increases since 2019

These new data represent notable increases since the CDC’s 2019 Report Card, which gave the U.S. population with diabetes in 2018 as 34.2 million, or 10.5% of the population, including 7.3 million undiagnosed. The prediabetes prevalence that year was 88 million.

Among children and adolescents younger than 20 years, 283,000, or 35 per 10,000 U.S. youths, had diagnosed diabetes in 2019. Of those, 244,000 had type 1 diabetes. Another 1.6 million adults aged 20 and older also reported having type 1 diabetes, comprising 5.7% of U.S. adults with diagnosed diabetes.

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

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. 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. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

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

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. 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. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

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

There’s overall agreement that iron deficiency is prevalent and portends a worse prognosis in patients with heart failure (HF), regardless of ejection fraction or anemia. What remains unclear, however, is which of the many definitions of iron deficiency most closely aligns with adverse outcomes.

Iron deficiency (ID) differs in chronic inflammatory conditions, such as chronic HF, and is defined in international guidelines as a ferritin less than 100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation (TSAT) less than 20%.

copyrightSaipg/iStockphoto

A new study examining four definitions of ID in more than 4,000 patients with HF revealed that TSAT and serum iron – but not guideline criteria – were independently associated with higher 5-year all-cause mortality, regardless of HF phenotype.

“The standard definition, the society guideline definition of iron deficiency, simply isn’t related to outcome at all. The lines for mortality are, more or less, superimposed,” senior author Andrew L. Clark, MD, Hull (England) University Teaching Hospital NHS Trust, told this news organization.

“So we do think, therefore, there’s a need for a rethink as to what constitutes a definition of iron definition in people with heart failure.”

The results were published in the Journal of the American College of Cardiology.

Previous studies have shown that guideline-defined ID is an independent predictor of mortality in chronic HF, but others have questioned its diagnostic and prognostic utility. A 2018 study using bone marrow iron staining as the gold standard showed that a TSAT of 19.8% or less or serum iron of 13 mcmol/L or less, but not ferritin, identified HF patients at the highest risk for death.

A 2016 report from the Hull LifeLab cohort also showed that the highest quintiles of ferritin had the worst all-cause and cardiovascular (CV) mortality.

Commenting on the new results, Maria Rosa Costanzo, MD, Midwest Cardiovascular Institute, Naperville, Ill., said “the first clinical implication is that we should not use these guidelines to define iron deficiency.

“The fundamental problem with the definition is that ferritin is not a good marker of iron deficiency because ferritin is an inflammatory marker,” she said. “So you could have high ferritin and still have iron deficiency because heart failure, like many other diseases, is an inflammatory state.”

In the present analysis of 4,422 patients referred to the Hull LifeLab clinic between 2001 and 2019, iron deficiency was defined using international guideline criteria, ferritin less than 100 ng/mL, TSAT less than 20%, and serum iron 13 mcmol/L or less.

In line with previous studies, the prevalence of ID was high, ranging from 44% to 68%, depending on the definition. ID was more common in women and in those with more severe symptoms, anemia, or preserved ejection fraction.

Overall, 5-year mortality was 34.5% (median follow-up, 49 months). Unadjusted mortality was lowest for patients with a serum ferritin less than 100 ng/mL and a TSAT greater than 20% and was highest for those with serum ferritin above 100 ng/mL with a TSAT less than 20%.

Serum iron levels and TSAT were highly correlated with each other (r = 0.92; P < .001). “Serum iron is almost entirely transferrin bound, and therefore a close association between serious iron and TSAT is not surprising,” noted the authors, led by Gabriele Masini, MD, University of Brescia (Italy).

After multivariate adjustment, TSAT less than 20% (hazard ratio, 1.27; P < .001) and serum iron of 13 mcmol/L or less (HR, 1.37; P < .001) were associated with greater all-cause mortality but not with CV mortality.

Serum ferritin less than 100 ng/mL tended to be associated with lower adjusted all-cause mortality (HR, 0.91; P = .09), whereas ferritin greater than 300 ng/mL was associated with lower all-cause (HR, 0.69, P < .001) and CV mortality (HR, 0.78; P = .048).

No association was found for guideline ID criteria and all-cause or CV mortality. Among patients fulfilling guideline ID criteria with a TSAT less than 20% and a ferritin 100 to 299 ng/mL, the adjusted hazard ratio for 5-year mortality was 1.82.
 

A ‘new iron age’

Although 3,011 (68%) patients met the guideline definition of ID, 32% of these patients had a TSAT of 20% or greater and serum iron above 13 mcmol/L, noted Dr. Costanzo.

“In other words, 30% of the patients do not have true iron deficiency,” she said. “If these patients are enrolled in trials of treatment for iron deficiency, they may spuriously reduce the efficacy of treatment.”

Intravenous iron has been shown to improve exercise capacity and quality of life in iron-deficient patients with HF in a series of trials, including FAIR-HF, CONFIRM-HF, and EFFECT-HF, and to reduce HF hospitalizations by 21% in the recent AFFIRM-AF trial.

Although from a single center, Dr. Clark said their findings are robust and hoped they spur a reanalysis of the data from older intravenous iron trials, as well as the IRONMAN trial expected later this year in patients with TSAT less than 20% or ferritin less than 100 ng/L.

“I would very much like to encourage industry to take our study and run with it a little bit and see if we can actually persuade them to rerun studies, maybe even very small-scale studies with a couple hundred patients, to see what the signal is using our definition of iron deficiency and seeing if we get a more striking immediate consequence from IV iron treatment as a result,” he said. “Because we think that we’ve now been able to define a group of patients whose iron deficiency is giving them a very poor prognosis and they, therefore, have much more to gain.”

In an accompanying editorial, Dr. Costanzo and coauthor James Januzzi, MD, of Massachusetts General Hospital and Harvard Medical School, both in Boston, also called for further research into better ID definitions and treatments.

“Diagnostically, soluble transferrin receptor levels may have the strongest correlation with the gold standard of bone marrow iron deficit, whereas new treatments, such as blockade of hepcidin, a key modulator of iron absorption and distribution, may emerge as an effective treatment for both absolute and functional ID,” they wrote.

“Ultimately, the study by Masini et al. places us squarely in a new iron age and underscores the great need for more investigation of the pathophysiology, clinical consequences, and treatment of iron deficiency in all patients with HF,” Dr. Costanzo and Dr. Januzzi concluded.

Dr. Masini reported having no relevant financial relationships. 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. Costanzo is a member of the board of directors for Nuwellis; is a consultant for Boehringer Ingelheim, V-Wave, and Nuwellis; and has received grant support from Novartis, Bayer, V-Wave, Nuwellis, and Abbott.

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

Japanese researchers say the Omicron variant survives longer on plastic and skin than other COVID-19 variants, one possible explanation for why Omicron has spread so rapidly around the world.

In a lab experiment, samples of different variants were applied to pieces of plastic and human skin collected from autopsies, researchers from Kyoto Prefectural University of Medicine wrote in bioRxiv. A variant “survived” until it could no longer be detected on the surface.

“This study showed that the Omicron variant also has the highest environmental stability among VOCs (variants of concern), which suggests that this high stability might also be one of the factors that have allowed the Omicron variant to replace the Delta variant and spread rapidly,” the researchers wrote.

On plastic, the Omicron variant samples survived an average of 193.5 hours, a little more than 8 days. By comparison, the other survival times on plastic were 56 hours for the original COVID strain, 191.3 hours for Alpha, 156.6 hours for Beta, 59.3 hours for Gamma, and 114 hours for Delta.

On skin samples, the Omicron samples survived an average of 21.1 hours. The other variants had these average survival times on skin: 8.6 hours for the original version, 19.6 hours for Alpha, 19.1 hours for Beta, 11 hours for Gamma, and 16.8 hours for Delta.

The study found that the variants had more resistance to ethanol than the original strain of COVID. That said, all COVID samples were inactivated after being exposed to alcohol-based hand sanitizers for 15 seconds.

“Therefore, it is highly recommended that current infection control (hand hygiene) practices use disinfectants ... as proposed by the World Health Organization,” the researchers said.

The study has not been peer-reviewed.

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

Japanese researchers say the Omicron variant survives longer on plastic and skin than other COVID-19 variants, one possible explanation for why Omicron has spread so rapidly around the world.

In a lab experiment, samples of different variants were applied to pieces of plastic and human skin collected from autopsies, researchers from Kyoto Prefectural University of Medicine wrote in bioRxiv. A variant “survived” until it could no longer be detected on the surface.

“This study showed that the Omicron variant also has the highest environmental stability among VOCs (variants of concern), which suggests that this high stability might also be one of the factors that have allowed the Omicron variant to replace the Delta variant and spread rapidly,” the researchers wrote.

On plastic, the Omicron variant samples survived an average of 193.5 hours, a little more than 8 days. By comparison, the other survival times on plastic were 56 hours for the original COVID strain, 191.3 hours for Alpha, 156.6 hours for Beta, 59.3 hours for Gamma, and 114 hours for Delta.

On skin samples, the Omicron samples survived an average of 21.1 hours. The other variants had these average survival times on skin: 8.6 hours for the original version, 19.6 hours for Alpha, 19.1 hours for Beta, 11 hours for Gamma, and 16.8 hours for Delta.

The study found that the variants had more resistance to ethanol than the original strain of COVID. That said, all COVID samples were inactivated after being exposed to alcohol-based hand sanitizers for 15 seconds.

“Therefore, it is highly recommended that current infection control (hand hygiene) practices use disinfectants ... as proposed by the World Health Organization,” the researchers said.

The study has not been peer-reviewed.

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

Japanese researchers say the Omicron variant survives longer on plastic and skin than other COVID-19 variants, one possible explanation for why Omicron has spread so rapidly around the world.

In a lab experiment, samples of different variants were applied to pieces of plastic and human skin collected from autopsies, researchers from Kyoto Prefectural University of Medicine wrote in bioRxiv. A variant “survived” until it could no longer be detected on the surface.

“This study showed that the Omicron variant also has the highest environmental stability among VOCs (variants of concern), which suggests that this high stability might also be one of the factors that have allowed the Omicron variant to replace the Delta variant and spread rapidly,” the researchers wrote.

On plastic, the Omicron variant samples survived an average of 193.5 hours, a little more than 8 days. By comparison, the other survival times on plastic were 56 hours for the original COVID strain, 191.3 hours for Alpha, 156.6 hours for Beta, 59.3 hours for Gamma, and 114 hours for Delta.

On skin samples, the Omicron samples survived an average of 21.1 hours. The other variants had these average survival times on skin: 8.6 hours for the original version, 19.6 hours for Alpha, 19.1 hours for Beta, 11 hours for Gamma, and 16.8 hours for Delta.

The study found that the variants had more resistance to ethanol than the original strain of COVID. That said, all COVID samples were inactivated after being exposed to alcohol-based hand sanitizers for 15 seconds.

“Therefore, it is highly recommended that current infection control (hand hygiene) practices use disinfectants ... as proposed by the World Health Organization,” the researchers said.

The study has not been peer-reviewed.

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

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

More steps per day, particularly at a higher intensity, may reduce the risk of type 2 diabetes in older women, based on a prospective cohort study.

The link between daily stepping and diabetes was not significantly modified by body mass index (BMI) or other common diabetes risk factors, suggesting that the relationship is highly generalizable, lead author Alexis C. Garduno, MPH, a PhD student at the University of California, San Diego, and colleagues reported.

“Physical activity is a key modifiable behavior for diabetes prevention and management,” the investigators wrote in Diabetes Care. “Many prevention studies have demonstrated that regular physical activity, along with improved diet, reduces the risk of diabetes in adults. ... To the best of our knowledge, there are few studies examining the association between objectively measured steps per day and incident diabetes in a community-based setting.”

To this end, the investigators analyzed data from 4,838 older, community-living women in the Objective Physical Activity and Cardiovascular Health Study. Upon enrollment, women were without physician-diagnosed diabetes and had a mean age of 78.9 years. For 1 week, participants wore ActiGraph GT3X+ accelerometers to measure steps per day, as well as step intensity, graded as light or moderate to vigorous.

The relationship between daily activity and diabetes was analyzed using three multivariate models: The first included race/ethnicity and age; the second also included family history of diabetes, education, physical functioning, self-rated health, smoking status, and alcohol consumption; and the third added BMI, “a potential mediator in the causal pathway between steps per day and diabetes,” the investigators wrote.

Participants took an average of 3,729 steps per day, divided roughly evenly between light and moderate to vigorous intensity.

After a median follow-up of 5.7 years, 8.1% of women developed diabetes. The least-adjusted model showed a 14% reduction in diabetes risk per 2,000 steps (hazard ratio, 0.86; 95% confidence interval, 0.80-0.92; P = .007), whereas the second model, adjusting for more confounding variables, showed a 12% reduction in diabetes risk per 2,000 steps (HR, 0.88; 95% CI, 0.78-1.00; P = .045).

The final model, which added BMI, showed a 10% reduction in risk, although it didn’t reach statistical significance (HR, 0.90; 95% CI, 0.80-1.02; P = .11). Furthermore, accelerated failure time models suggested that BMI did not significantly impact the link between steps and diabetes (proportion mediated, 17.7%;95% CI, –55.0 to 142.0; P = .09). Further analyses also found no significant interactions between BMI or other possible confounders.

“The steps per day–diabetes association was not modified by age, race/ethnicity, BMI, physical functioning, or family history of diabetes, which supports the generalizability of these findings to community-living older women,” the investigators wrote.

Increased stepping intensity also appeared to lower risk of diabetes. After adjusting for confounding variables, light stepping was not linked to reduced risk (HR, 0.97; 95% CI, 0.73-1.29; P = .83), whereas moderate to vigorous stepping reduced risk by 14% per 2,000 steps (HR, 0.86; 95% CI, 0.74-1.00; P = .04).

“This study provides evidence supporting an association between steps per day and lower incident diabetes,” the investigators concluded. “While further work is needed to identify whether there is a minimum number of steps per day that results in a clinically significant reduction of diabetes and to evaluate the role that step intensity plays in diabetes etiology for older adults, findings from this study suggest that moderate-vigorous–intensity steps may be more important than lower-intensity steps with respect to incident diabetes. Steps per day–based interventions are needed to advance diabetes prevention science in older adults.”

The study was supported by the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the Tobacco-Related Disease Research Program, and others. The investigators had no potential conflicts of interest.

More steps per day, particularly at a higher intensity, may reduce the risk of type 2 diabetes in older women, based on a prospective cohort study.

The link between daily stepping and diabetes was not significantly modified by body mass index (BMI) or other common diabetes risk factors, suggesting that the relationship is highly generalizable, lead author Alexis C. Garduno, MPH, a PhD student at the University of California, San Diego, and colleagues reported.

“Physical activity is a key modifiable behavior for diabetes prevention and management,” the investigators wrote in Diabetes Care. “Many prevention studies have demonstrated that regular physical activity, along with improved diet, reduces the risk of diabetes in adults. ... To the best of our knowledge, there are few studies examining the association between objectively measured steps per day and incident diabetes in a community-based setting.”

To this end, the investigators analyzed data from 4,838 older, community-living women in the Objective Physical Activity and Cardiovascular Health Study. Upon enrollment, women were without physician-diagnosed diabetes and had a mean age of 78.9 years. For 1 week, participants wore ActiGraph GT3X+ accelerometers to measure steps per day, as well as step intensity, graded as light or moderate to vigorous.

The relationship between daily activity and diabetes was analyzed using three multivariate models: The first included race/ethnicity and age; the second also included family history of diabetes, education, physical functioning, self-rated health, smoking status, and alcohol consumption; and the third added BMI, “a potential mediator in the causal pathway between steps per day and diabetes,” the investigators wrote.

Participants took an average of 3,729 steps per day, divided roughly evenly between light and moderate to vigorous intensity.

After a median follow-up of 5.7 years, 8.1% of women developed diabetes. The least-adjusted model showed a 14% reduction in diabetes risk per 2,000 steps (hazard ratio, 0.86; 95% confidence interval, 0.80-0.92; P = .007), whereas the second model, adjusting for more confounding variables, showed a 12% reduction in diabetes risk per 2,000 steps (HR, 0.88; 95% CI, 0.78-1.00; P = .045).

The final model, which added BMI, showed a 10% reduction in risk, although it didn’t reach statistical significance (HR, 0.90; 95% CI, 0.80-1.02; P = .11). Furthermore, accelerated failure time models suggested that BMI did not significantly impact the link between steps and diabetes (proportion mediated, 17.7%;95% CI, –55.0 to 142.0; P = .09). Further analyses also found no significant interactions between BMI or other possible confounders.

“The steps per day–diabetes association was not modified by age, race/ethnicity, BMI, physical functioning, or family history of diabetes, which supports the generalizability of these findings to community-living older women,” the investigators wrote.

Increased stepping intensity also appeared to lower risk of diabetes. After adjusting for confounding variables, light stepping was not linked to reduced risk (HR, 0.97; 95% CI, 0.73-1.29; P = .83), whereas moderate to vigorous stepping reduced risk by 14% per 2,000 steps (HR, 0.86; 95% CI, 0.74-1.00; P = .04).

“This study provides evidence supporting an association between steps per day and lower incident diabetes,” the investigators concluded. “While further work is needed to identify whether there is a minimum number of steps per day that results in a clinically significant reduction of diabetes and to evaluate the role that step intensity plays in diabetes etiology for older adults, findings from this study suggest that moderate-vigorous–intensity steps may be more important than lower-intensity steps with respect to incident diabetes. Steps per day–based interventions are needed to advance diabetes prevention science in older adults.”

The study was supported by the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the Tobacco-Related Disease Research Program, and others. The investigators had no potential conflicts of interest.

More steps per day, particularly at a higher intensity, may reduce the risk of type 2 diabetes in older women, based on a prospective cohort study.

The link between daily stepping and diabetes was not significantly modified by body mass index (BMI) or other common diabetes risk factors, suggesting that the relationship is highly generalizable, lead author Alexis C. Garduno, MPH, a PhD student at the University of California, San Diego, and colleagues reported.

“Physical activity is a key modifiable behavior for diabetes prevention and management,” the investigators wrote in Diabetes Care. “Many prevention studies have demonstrated that regular physical activity, along with improved diet, reduces the risk of diabetes in adults. ... To the best of our knowledge, there are few studies examining the association between objectively measured steps per day and incident diabetes in a community-based setting.”

To this end, the investigators analyzed data from 4,838 older, community-living women in the Objective Physical Activity and Cardiovascular Health Study. Upon enrollment, women were without physician-diagnosed diabetes and had a mean age of 78.9 years. For 1 week, participants wore ActiGraph GT3X+ accelerometers to measure steps per day, as well as step intensity, graded as light or moderate to vigorous.

The relationship between daily activity and diabetes was analyzed using three multivariate models: The first included race/ethnicity and age; the second also included family history of diabetes, education, physical functioning, self-rated health, smoking status, and alcohol consumption; and the third added BMI, “a potential mediator in the causal pathway between steps per day and diabetes,” the investigators wrote.

Participants took an average of 3,729 steps per day, divided roughly evenly between light and moderate to vigorous intensity.

After a median follow-up of 5.7 years, 8.1% of women developed diabetes. The least-adjusted model showed a 14% reduction in diabetes risk per 2,000 steps (hazard ratio, 0.86; 95% confidence interval, 0.80-0.92; P = .007), whereas the second model, adjusting for more confounding variables, showed a 12% reduction in diabetes risk per 2,000 steps (HR, 0.88; 95% CI, 0.78-1.00; P = .045).

The final model, which added BMI, showed a 10% reduction in risk, although it didn’t reach statistical significance (HR, 0.90; 95% CI, 0.80-1.02; P = .11). Furthermore, accelerated failure time models suggested that BMI did not significantly impact the link between steps and diabetes (proportion mediated, 17.7%;95% CI, –55.0 to 142.0; P = .09). Further analyses also found no significant interactions between BMI or other possible confounders.

“The steps per day–diabetes association was not modified by age, race/ethnicity, BMI, physical functioning, or family history of diabetes, which supports the generalizability of these findings to community-living older women,” the investigators wrote.

Increased stepping intensity also appeared to lower risk of diabetes. After adjusting for confounding variables, light stepping was not linked to reduced risk (HR, 0.97; 95% CI, 0.73-1.29; P = .83), whereas moderate to vigorous stepping reduced risk by 14% per 2,000 steps (HR, 0.86; 95% CI, 0.74-1.00; P = .04).

“This study provides evidence supporting an association between steps per day and lower incident diabetes,” the investigators concluded. “While further work is needed to identify whether there is a minimum number of steps per day that results in a clinically significant reduction of diabetes and to evaluate the role that step intensity plays in diabetes etiology for older adults, findings from this study suggest that moderate-vigorous–intensity steps may be more important than lower-intensity steps with respect to incident diabetes. Steps per day–based interventions are needed to advance diabetes prevention science in older adults.”

The study was supported by the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the Tobacco-Related Disease Research Program, and others. The investigators had no potential conflicts of interest.

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

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

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

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

A new statement from the U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation (AFib) in asymptomatic adults.

The guidance is similar to the task force’s 2018 statement on screening for AFib with electrocardiography in asymptomatic adults 65 years or older, but lowers the inclusion age to adults 50 years or older.

“This 2021 evidence review included searching for evidence on additional screening methods such as automated blood pressure cuffs, pulse oximeters, and consumer devices such as smartwatches and smartphone apps. However, even with this expanded scope, the USPSTF did not find evidence to recommend for or against screening for AF,” the task force states.

The prevalence of increases in age from less than 0.2% in adults younger than 55 years to about 10% in those 85 years or older, the group says. The prevalence is higher in men than in women, but it is uncertain if it differs by race and ethnicity.

Although AFib substantially increases the risk for stroke, the stroke risk associated with subclinical AFib, particularly that of shorter duration lasting less than 24 hours or of lower burden, as might be detected by some screening approaches, is “uncertain,” the task force adds.

The updated recommendations were published online in JAMA, along with a separate evidence report and editorial.

The task force reviewed 26 studies in 113,784 patients, including 12 new to the update.

Studies showed that systematic screening detected significantly more AFib than no screening or pulse palpation (absolute difference, 1.0%-4.8% over up to 12 months). In two of the trials, however, only 10.7% and 44.5% of participants actually received the screening test.

The review included three randomized trials of screening vs. no screening that reported on health outcomes, but only one, STROKESTOP, was powered for health outcomes. It found a significantly lower risk for the primary composite endpoint of ischemic or hemorrhagic stroke, system embolism, bleeding leading to hospitalization, and all-cause mortality with twice-daily intermittent single-lead ECG monitoring for 14 days, compared with no screening. However, there were no significant differences in any of the individual outcomes of the composite endpoint.

“Additionally, and probably the most important thing to appreciate for the STROKESTOP study is that it has several limitations,” task force member Gbenga Ogedegbe, MD, MPH, of New York University told this news organization. The intervention was not masked, and outcomes weren’t centrally adjudicated.

Further, “about 11% of patients in the trial had a history of transient ischemic attack (TIA), stroke, or embolism and the population that we’re looking at within the task force are people without symptoms or history of stroke or ischemic attack,” he said. “That’s the fundamental difference here. So those limitations make it difficult to say that STROKESTOP actually has benefit.”

Notably absent from the review was the recent LOOP study, which found no significant benefit on outcomes with continuous monitoring with an implantable loop recorder (ILR) over usual care in older adults.

While it “offers some context for this issue,” it was not eligible for inclusion because 25% of the population had a prior history of stroke, TIA, or embolism and “because this screening approach may not be feasible for primary care settings,” lead author of the Evidence Report Leila Kahwati, MD, MPH, from RTI International’s Social and Health Organizational Research and Evaluation Program and the University of North Carolina at Chapel Hill, explained in an email.

Treatment with warfarin (mean, 1.5 years) was associated with a lower risk for ischemic stroke (relative risk, 0.32) and all-cause mortality (relative risk, 0.68), while direct oral anticoagulants were associated with a lower incidence of stroke (adjusted odds ratio range, 0.32-0.44). Patients had an increased risk for major bleeding with both warfarin (pooled relative risk, 1.8) and direct-acting oral anticoagulants (odds ratio, 1.38-2.21), but confidence intervals did not exclude a null effect.

The USPSTF found no trials that reported on the benefits of anticoagulation therapy in screen-detected patients.

In an accompanying editorial Philip Greenland, MD, points out that the task force’s conclusion differs from the 2020 European Society of Cardiology AFib guideline, which endorses opportunistic screening for AFib by pulse palpation or ECG rhythm strip in patients 65 years or older (class I recommendation) and advises that clinicians consider systematic ECG screening to detect AFib in people 75 years or older, or those at high risk for stroke (class IIa).

To possibly resolve whether screening for AFib in asymptomatic patients is justified, “future trials may need to consider enrolling only higher risk patients and identifying those with AF of longer duration,” said Dr. Greenland, JAMA editor and professor of preventive medicine and medicine at Northwestern University, Chicago.

“One important point raised by the LOOP trial is whether there is a threshold for AF duration that is most strongly associated with stroke risk and therefore most likely to benefit from anticoagulation,” he writes. Indeed, the LOOP authors themselves questioned whether the trial’s short AFib duration of 6 minutes may have led to many low-risk patients being diagnosed and treated.

“Additionally, trials need to recognize the need for longer monitoring periods (preferably continuous), and perhaps novel wearables will allow long-term monitoring, with accurate interpretation of the ECG and long-term adherence,” Dr. Greenland said.

In a related editorial in JAMA Internal Medicine, John Mandrola, MD, Baptist Health Louisville, Ky., and Andrew Foy, MD, Pennsylvania State University, Hershey, point out that continuous ILR monitoring in the LOOP trial found threefold more AFib and led to 2.7-fold higher rates of oral anticoagulation use, compared with standard care. Yet, there was no statistically significant difference in stroke reduction, and the 20% relative reduction in thromboembolic complications in the screened group was offset by a 26% relative increase in major bleeding.

“Perhaps the most remarkable aspect of the AF screening trials is that as the tools for screening improve, from a single 12-lead ECG to 14-day recordings and then the always-on ILR, more AF is detected and more [oral anticoagulant] is used, yet there is little demonstrable improvement in outcomes,” Dr. Mandrola and Dr. Foy write.

The editorialists also point to the potential for rhythm monitoring to lead to misdiagnosis and downstream cascades of care. “If you assume a 2% AF prevalence, even a device with 98% specificity will misdiagnose approximately 2000 individuals for every million screened.”

Dr. Mandrola told this news organization that the “greatest value” of these reports on AF screening and the critical appraisal of them is as an exercise in thinking about the limits of screening for disease. As James Maxwell Glover Wilson and Gunner Jungner wrote in their 1968 textbook, “Principles and Practice of Screening for Disease”: “in theory, screening is an admirable method of combating disease … [but] in practice, there are snags.”

“It would be good for the public to understand these snags…because they also apply to cancer, coronary calcium testing, and vascular screening as well,” Dr. Mandrola said.

Asked whether it’s possible to put the genie back in the bottle now that every other patient in clinic may have an ECG on their wrist, Dr. Ogedegbe said, “if a patient has no history of stroke or TIA and is 50 years or older, really, monitoring with these devices for AFib, there’s no evidence for or against doing that. Ultimately, the clinician has got to use their clinical judgment in talking to these patients.”

A related editorial in JAMA Cardiology suggests that, to be effective, the movement toward consumer-based screening must first show that such an approach improves outcomes and must deal with the paradox that those at highest risk for AFib and AFib-related stroke may be the least likely to own these technologies unless supported by the healthcare system.

“In addition, appropriate care pathways for confirming the diagnosis and, if necessary, initiating appropriate treatment in individuals with positive findings will need to be established,” Rod Passman, MD, Northwestern University, and Ben Freedman, MBBS, PhD, University of Sydney, Australia, say. “It will also be critical to ensure that device costs and variable technological literacy do not create barriers to making screening accessible to all those at risk.”

Finally, in a related editorial in JAMA Network Open Matthew Kalscheur, MD, and Zachary D. Goldberger, MD, both from the University of Wisconsin-Madison, say the potential benefits of early AFib detection should extend beyond stroke prevention.

“Patients identified with AF likely would benefit from targeted management of modifiable risk factors that contribute to AF, including obesity, hypertension, alcohol use, sleep apnea, smoking, and diabetes,” they write.

All members of the USPSTF receive travel reimbursement and an honorarium for participating in USPSTF meetings. Dr. Ogedegbe has a study included in the Evidence-based Practice Center report for this topic. Dr. Kahwati reported no relevant financial conflicts of interest. Dr. Greenland reported receiving research grants from the National Institutes of Health and from the American Heart Association. Dr. Mandrola is a regular contributor to this news organization. Dr. Foy, Dr. Kalscheur, and Dr. Goldberger reported no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

A new, highly contagious subvariant of Omicron has emerged, which some have begun calling “son of Omicron,” but public health officials say it’s too soon to tell what kind of real threat, if any, this new strain will present.

In the meantime, it’s worth watching BA.2, the World Health Organization said. The subvariant has been identified across at least 40 countries, including three cases reported in Houston and several in Washington state.

BA.2 accounts for only a small minority of reported cases so far, including 5% in India, 4% of those in the United Kingdom, and 2% each of cases in Sweden and Singapore.

The one exception is Denmark, a country with robust genetic sequencing abilities, where estimates range from 50% to 81% of cases.

The news throws a little more uncertainty into an already uncertain situation, including how close the world might be to a less life-altering infectious disease.

For example, the world is at an ideal point for a new variant to emerge, WHO Director General Tedros Adhanom Ghebreyesus, PhD, said during a Jan. 24 meeting of the WHO executive board. He also said it’s too early to call an “end game” to the pandemic.

Similarly, Anthony S. Fauci, MD, said on Jan. 19 that it remained “an open question” whether the Omicron variant could hasten endemic COVID-19, a situation where the virus still circulates but is much less disruptive to everyday life.
 

No Pi for you

This could be the first time a coronavirus subvariant rises to the level of a household name, or – if previous variants of the moment have shown us – it could recede from the spotlight.

For example, a lot of focus on the potential of the Mu variant to wreak havoc fizzled out a few weeks after the WHO listed it as a variant of interest on Aug. 30.

Subvariants can feature mutations and other small differences but are not distinct enough from an existing strain to be called a variant on their own and be named after the next letter in the Greek alphabet. That’s why BA.2 is not called the “Pi variant.”

Predicting what’s next for the coronavirus has puzzled many experts throughout the pandemic. That is why many public health officials wait for the WHO to officially designate a strain as a variant of interest or variant of concern before taking action.

At the moment with BA.2, it seems close monitoring is warranted.

Because it’s too early to call, expert predictions about BA.2 vary widely, from worry to cautious optimism.

For example, early data indicates that BA.2 could be more worrisome than original Omicron, Eric Feigl-Ding, ScD, an epidemiologist and health economist, said on Twitter.

Information from Denmark seems to show BA.2 either has “much faster transmission or it evades immunity even more,” he said.

The same day, Jan. 23, Dr. Feigl-Ding tweeted that other data shows the subvariant can spread twice as fast as Omicron, which was already much more contagious than previous versions of the virus.

At the same time, other experts appear less concerned. Robert Garry, PhD, a virologist at Tulane University, New Orleans, told the Washington Post that there is no reason to think BA.2 will be any worse than the original Omicron strain.

So which expert predictions will come closer to BA.2’s potential? For now, it’s just a watch-and-see situation.

For updated information, the website outbreak.info tracks BA.2’s average daily and cumulative prevalence in the United States and in other locations.

Also, if and when WHO experts decide to elevate BA.2 to a variant of interest or a variant of concern, it will be noted on its coronavirus variant tracking website.

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

A new, highly contagious subvariant of Omicron has emerged, which some have begun calling “son of Omicron,” but public health officials say it’s too soon to tell what kind of real threat, if any, this new strain will present.

In the meantime, it’s worth watching BA.2, the World Health Organization said. The subvariant has been identified across at least 40 countries, including three cases reported in Houston and several in Washington state.

BA.2 accounts for only a small minority of reported cases so far, including 5% in India, 4% of those in the United Kingdom, and 2% each of cases in Sweden and Singapore.

The one exception is Denmark, a country with robust genetic sequencing abilities, where estimates range from 50% to 81% of cases.

The news throws a little more uncertainty into an already uncertain situation, including how close the world might be to a less life-altering infectious disease.

For example, the world is at an ideal point for a new variant to emerge, WHO Director General Tedros Adhanom Ghebreyesus, PhD, said during a Jan. 24 meeting of the WHO executive board. He also said it’s too early to call an “end game” to the pandemic.

Similarly, Anthony S. Fauci, MD, said on Jan. 19 that it remained “an open question” whether the Omicron variant could hasten endemic COVID-19, a situation where the virus still circulates but is much less disruptive to everyday life.
 

No Pi for you

This could be the first time a coronavirus subvariant rises to the level of a household name, or – if previous variants of the moment have shown us – it could recede from the spotlight.

For example, a lot of focus on the potential of the Mu variant to wreak havoc fizzled out a few weeks after the WHO listed it as a variant of interest on Aug. 30.

Subvariants can feature mutations and other small differences but are not distinct enough from an existing strain to be called a variant on their own and be named after the next letter in the Greek alphabet. That’s why BA.2 is not called the “Pi variant.”

Predicting what’s next for the coronavirus has puzzled many experts throughout the pandemic. That is why many public health officials wait for the WHO to officially designate a strain as a variant of interest or variant of concern before taking action.

At the moment with BA.2, it seems close monitoring is warranted.

Because it’s too early to call, expert predictions about BA.2 vary widely, from worry to cautious optimism.

For example, early data indicates that BA.2 could be more worrisome than original Omicron, Eric Feigl-Ding, ScD, an epidemiologist and health economist, said on Twitter.

Information from Denmark seems to show BA.2 either has “much faster transmission or it evades immunity even more,” he said.

The same day, Jan. 23, Dr. Feigl-Ding tweeted that other data shows the subvariant can spread twice as fast as Omicron, which was already much more contagious than previous versions of the virus.

At the same time, other experts appear less concerned. Robert Garry, PhD, a virologist at Tulane University, New Orleans, told the Washington Post that there is no reason to think BA.2 will be any worse than the original Omicron strain.

So which expert predictions will come closer to BA.2’s potential? For now, it’s just a watch-and-see situation.

For updated information, the website outbreak.info tracks BA.2’s average daily and cumulative prevalence in the United States and in other locations.

Also, if and when WHO experts decide to elevate BA.2 to a variant of interest or a variant of concern, it will be noted on its coronavirus variant tracking website.

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

A new, highly contagious subvariant of Omicron has emerged, which some have begun calling “son of Omicron,” but public health officials say it’s too soon to tell what kind of real threat, if any, this new strain will present.

In the meantime, it’s worth watching BA.2, the World Health Organization said. The subvariant has been identified across at least 40 countries, including three cases reported in Houston and several in Washington state.

BA.2 accounts for only a small minority of reported cases so far, including 5% in India, 4% of those in the United Kingdom, and 2% each of cases in Sweden and Singapore.

The one exception is Denmark, a country with robust genetic sequencing abilities, where estimates range from 50% to 81% of cases.

The news throws a little more uncertainty into an already uncertain situation, including how close the world might be to a less life-altering infectious disease.

For example, the world is at an ideal point for a new variant to emerge, WHO Director General Tedros Adhanom Ghebreyesus, PhD, said during a Jan. 24 meeting of the WHO executive board. He also said it’s too early to call an “end game” to the pandemic.

Similarly, Anthony S. Fauci, MD, said on Jan. 19 that it remained “an open question” whether the Omicron variant could hasten endemic COVID-19, a situation where the virus still circulates but is much less disruptive to everyday life.
 

No Pi for you

This could be the first time a coronavirus subvariant rises to the level of a household name, or – if previous variants of the moment have shown us – it could recede from the spotlight.

For example, a lot of focus on the potential of the Mu variant to wreak havoc fizzled out a few weeks after the WHO listed it as a variant of interest on Aug. 30.

Subvariants can feature mutations and other small differences but are not distinct enough from an existing strain to be called a variant on their own and be named after the next letter in the Greek alphabet. That’s why BA.2 is not called the “Pi variant.”

Predicting what’s next for the coronavirus has puzzled many experts throughout the pandemic. That is why many public health officials wait for the WHO to officially designate a strain as a variant of interest or variant of concern before taking action.

At the moment with BA.2, it seems close monitoring is warranted.

Because it’s too early to call, expert predictions about BA.2 vary widely, from worry to cautious optimism.

For example, early data indicates that BA.2 could be more worrisome than original Omicron, Eric Feigl-Ding, ScD, an epidemiologist and health economist, said on Twitter.

Information from Denmark seems to show BA.2 either has “much faster transmission or it evades immunity even more,” he said.

The same day, Jan. 23, Dr. Feigl-Ding tweeted that other data shows the subvariant can spread twice as fast as Omicron, which was already much more contagious than previous versions of the virus.

At the same time, other experts appear less concerned. Robert Garry, PhD, a virologist at Tulane University, New Orleans, told the Washington Post that there is no reason to think BA.2 will be any worse than the original Omicron strain.

So which expert predictions will come closer to BA.2’s potential? For now, it’s just a watch-and-see situation.

For updated information, the website outbreak.info tracks BA.2’s average daily and cumulative prevalence in the United States and in other locations.

Also, if and when WHO experts decide to elevate BA.2 to a variant of interest or a variant of concern, it will be noted on its coronavirus variant tracking website.

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

Two years ago, I argued that independent care from nurse practitioners (NPs) and physician assistants (PAs) would not have ill effects on health outcomes. To the surprise of no one, NPs and PAs embraced the argument; physicians clobbered it.

My case had three pegs: One was that medicine isn’t rocket science and clinicians control a lot less than we think we do. The second peg was that technology levels the playing field of clinical care. High-sensitivity troponin assays, for instance, make missing MI a lot less likely. The third peg was empirical: Studies have found little difference in MD versus non–MD-led care. Looking back, I now see empiricism as the weakest part of the argument because the studies had so many limitations.

I update this viewpoint now because health care is increasingly delivered by NPs and PAs. And there are two concerning trends regarding NP education and experience. First is that nurses are turning to advanced practitioner training earlier in their careers – without gathering much bedside experience. And these training programs are increasingly likely to be online, with minimal hands-on clinical tutoring. 

Education and experience pop in my head often. Not every day, but many days I think back to my lucky 7 years in Indiana learning under the supervision of master clinicians – at a time when trainees were allowed the leeway to make decisions ... and mistakes. Then, when I joined private practice, I continued to learn from experienced practitioners.

It would be foolish to argue that training and experience aren’t important.

But here’s the thing: I still don’t see average health outcomes declining as a result of the rise in NPs and PAs. And even if I did, it wouldn’t matter. The rise in nonphysician care will not be undone, at least any time soon.

I will make three points: First, I will bolster two of my old arguments as to why we shouldn’t be worried about non-MD clinicians, then I will propose some ideas to increase confidence in NP and PA care.
 

Health care does not equal health

On the matter of how much clinicians affect outcomes, a recently published randomized controlled trial performed in India found that subsidizing insurance care led to increased utilization of hospital services but had no significant effect on health outcomes. This follows the RAND and Oregon Health Insurance studies in the United States, which largely reported similar results.

It’s about the delta

Logos trumps pathos. Sure, my physician colleagues can tell scary anecdotes of bad outcomes caused by an inexperienced NP or PA. I would counter that by saying I have sat on our hospital’s peer review committee for 2 decades, including the era before NPs or PAs were practicing, and I have plenty of stories of physician errors. These include, of course, my own errors.

Logos: We must consider the difference between non–MD-led care and MD-led care.

My arguments from 2020 remain relevant today. Most medical problems are not engineering puzzles. Many, perhaps most, patients fall into an easy protocol – say, chest pain, dyspnea, or atrial fibrillation. With basic training, a motivated serious person quickly gains skill in recognizing and treating everyday problems.

And just 2 years on, technology further levels the playing field. Consider radiology in 2022 – it’s easy to take for granted the speed of the CT scan, the fidelity of the MRI, and the easy access to both in the U.S. hospital system. Less experienced clinicians have never had more tools to assist with diagnostics and therapeutics.

The expansion of team-based care has also mitigated the effects of inexperience. It took Americans longer than Canadians to figure out how helpful pharmacists could be. Pharmacists in my hospital now help us dose complicated medicines and protect us against prescribing errors.

Then there is the immediate access to online information. Gone are the days when you had to memorize long-QT syndromes. Book knowledge – that I spent years acquiring – now comes in seconds. The other day an NP corrected me. I asked, Are you sure? Boom, she took out her phone and showed me the evidence.

In sum, if it were even possible to measure the clinical competence of care from NP and PA versus physicians, there would be two bell-shaped curves with a tremendous amount of overlap. And that overlap would steadily increase as a given NP or PA gathered experience. (The NP in our electrophysiology division has more than 25 years’ experience in heart rhythm care, and it is common for colleagues to call her before one of us docs. Rightly so.)
 

Three basic proposals regarding NP and PA care

To ensure quality of care, I have three proposals.

It has always seemed strange to me that an NP or PA can flip from one field to another without a period of training. I can’t just change practice from electrophysiology to dermatology without doing a residency. But NPs and PAs can.

My first proposal would be that NPs and PAs spend a substantial period of training in a field before practice – a legit apprenticeship. The duration of this period is a matter of debate, but it ought to be standardized.

My second proposal is that, if physicians are required to pass certification exams, so should NPs. (PAs have an exam every 10 years.) The exam should be the same as (or very similar to) the physician exam, and it should be specific to their field of practice.

While I have argued (and still feel) that the American Board of Internal Medicine brand of certification is dubious, the fact remains that physicians must maintain proficiency in their field. Requiring NPs and PAs to do the same would help foster specialization. And while I can’t cite empirical evidence, specialization seems super-important. We have NPs at my hospital who have been in the same area for years, and they exude clinical competence.

Finally, I have come to believe that the best way for nearly any clinician to practice medicine is as part of a team. (The exception being primary care in rural areas where there are clinician shortages.)

On the matter of team care, I’ve practiced for a long time, but nearly every day I run situations by a colleague; often this person is an NP. The economist Friedrich Hayek proposed that dispersed knowledge always outpaces the wisdom of any individual. That notion pertains well to the increasing complexities and specialization of modern medical practice.

A person who commits to learning one area of medicine, enjoys helping people, asks often for help, and has the support of colleagues is set up to be a successful clinician – whether the letters after their name are APRN, PA, DO, or MD.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky. He did not report any relevant financial disclosures. A version of this article first appeared on Medscape.com.

Two years ago, I argued that independent care from nurse practitioners (NPs) and physician assistants (PAs) would not have ill effects on health outcomes. To the surprise of no one, NPs and PAs embraced the argument; physicians clobbered it.

My case had three pegs: One was that medicine isn’t rocket science and clinicians control a lot less than we think we do. The second peg was that technology levels the playing field of clinical care. High-sensitivity troponin assays, for instance, make missing MI a lot less likely. The third peg was empirical: Studies have found little difference in MD versus non–MD-led care. Looking back, I now see empiricism as the weakest part of the argument because the studies had so many limitations.

I update this viewpoint now because health care is increasingly delivered by NPs and PAs. And there are two concerning trends regarding NP education and experience. First is that nurses are turning to advanced practitioner training earlier in their careers – without gathering much bedside experience. And these training programs are increasingly likely to be online, with minimal hands-on clinical tutoring. 

Education and experience pop in my head often. Not every day, but many days I think back to my lucky 7 years in Indiana learning under the supervision of master clinicians – at a time when trainees were allowed the leeway to make decisions ... and mistakes. Then, when I joined private practice, I continued to learn from experienced practitioners.

It would be foolish to argue that training and experience aren’t important.

But here’s the thing: I still don’t see average health outcomes declining as a result of the rise in NPs and PAs. And even if I did, it wouldn’t matter. The rise in nonphysician care will not be undone, at least any time soon.

I will make three points: First, I will bolster two of my old arguments as to why we shouldn’t be worried about non-MD clinicians, then I will propose some ideas to increase confidence in NP and PA care.
 

Health care does not equal health

On the matter of how much clinicians affect outcomes, a recently published randomized controlled trial performed in India found that subsidizing insurance care led to increased utilization of hospital services but had no significant effect on health outcomes. This follows the RAND and Oregon Health Insurance studies in the United States, which largely reported similar results.

It’s about the delta

Logos trumps pathos. Sure, my physician colleagues can tell scary anecdotes of bad outcomes caused by an inexperienced NP or PA. I would counter that by saying I have sat on our hospital’s peer review committee for 2 decades, including the era before NPs or PAs were practicing, and I have plenty of stories of physician errors. These include, of course, my own errors.

Logos: We must consider the difference between non–MD-led care and MD-led care.

My arguments from 2020 remain relevant today. Most medical problems are not engineering puzzles. Many, perhaps most, patients fall into an easy protocol – say, chest pain, dyspnea, or atrial fibrillation. With basic training, a motivated serious person quickly gains skill in recognizing and treating everyday problems.

And just 2 years on, technology further levels the playing field. Consider radiology in 2022 – it’s easy to take for granted the speed of the CT scan, the fidelity of the MRI, and the easy access to both in the U.S. hospital system. Less experienced clinicians have never had more tools to assist with diagnostics and therapeutics.

The expansion of team-based care has also mitigated the effects of inexperience. It took Americans longer than Canadians to figure out how helpful pharmacists could be. Pharmacists in my hospital now help us dose complicated medicines and protect us against prescribing errors.

Then there is the immediate access to online information. Gone are the days when you had to memorize long-QT syndromes. Book knowledge – that I spent years acquiring – now comes in seconds. The other day an NP corrected me. I asked, Are you sure? Boom, she took out her phone and showed me the evidence.

In sum, if it were even possible to measure the clinical competence of care from NP and PA versus physicians, there would be two bell-shaped curves with a tremendous amount of overlap. And that overlap would steadily increase as a given NP or PA gathered experience. (The NP in our electrophysiology division has more than 25 years’ experience in heart rhythm care, and it is common for colleagues to call her before one of us docs. Rightly so.)
 

Three basic proposals regarding NP and PA care

To ensure quality of care, I have three proposals.

It has always seemed strange to me that an NP or PA can flip from one field to another without a period of training. I can’t just change practice from electrophysiology to dermatology without doing a residency. But NPs and PAs can.

My first proposal would be that NPs and PAs spend a substantial period of training in a field before practice – a legit apprenticeship. The duration of this period is a matter of debate, but it ought to be standardized.

My second proposal is that, if physicians are required to pass certification exams, so should NPs. (PAs have an exam every 10 years.) The exam should be the same as (or very similar to) the physician exam, and it should be specific to their field of practice.

While I have argued (and still feel) that the American Board of Internal Medicine brand of certification is dubious, the fact remains that physicians must maintain proficiency in their field. Requiring NPs and PAs to do the same would help foster specialization. And while I can’t cite empirical evidence, specialization seems super-important. We have NPs at my hospital who have been in the same area for years, and they exude clinical competence.

Finally, I have come to believe that the best way for nearly any clinician to practice medicine is as part of a team. (The exception being primary care in rural areas where there are clinician shortages.)

On the matter of team care, I’ve practiced for a long time, but nearly every day I run situations by a colleague; often this person is an NP. The economist Friedrich Hayek proposed that dispersed knowledge always outpaces the wisdom of any individual. That notion pertains well to the increasing complexities and specialization of modern medical practice.

A person who commits to learning one area of medicine, enjoys helping people, asks often for help, and has the support of colleagues is set up to be a successful clinician – whether the letters after their name are APRN, PA, DO, or MD.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky. He did not report any relevant financial disclosures. A version of this article first appeared on Medscape.com.

Two years ago, I argued that independent care from nurse practitioners (NPs) and physician assistants (PAs) would not have ill effects on health outcomes. To the surprise of no one, NPs and PAs embraced the argument; physicians clobbered it.

My case had three pegs: One was that medicine isn’t rocket science and clinicians control a lot less than we think we do. The second peg was that technology levels the playing field of clinical care. High-sensitivity troponin assays, for instance, make missing MI a lot less likely. The third peg was empirical: Studies have found little difference in MD versus non–MD-led care. Looking back, I now see empiricism as the weakest part of the argument because the studies had so many limitations.

I update this viewpoint now because health care is increasingly delivered by NPs and PAs. And there are two concerning trends regarding NP education and experience. First is that nurses are turning to advanced practitioner training earlier in their careers – without gathering much bedside experience. And these training programs are increasingly likely to be online, with minimal hands-on clinical tutoring. 

Education and experience pop in my head often. Not every day, but many days I think back to my lucky 7 years in Indiana learning under the supervision of master clinicians – at a time when trainees were allowed the leeway to make decisions ... and mistakes. Then, when I joined private practice, I continued to learn from experienced practitioners.

It would be foolish to argue that training and experience aren’t important.

But here’s the thing: I still don’t see average health outcomes declining as a result of the rise in NPs and PAs. And even if I did, it wouldn’t matter. The rise in nonphysician care will not be undone, at least any time soon.

I will make three points: First, I will bolster two of my old arguments as to why we shouldn’t be worried about non-MD clinicians, then I will propose some ideas to increase confidence in NP and PA care.
 

Health care does not equal health

On the matter of how much clinicians affect outcomes, a recently published randomized controlled trial performed in India found that subsidizing insurance care led to increased utilization of hospital services but had no significant effect on health outcomes. This follows the RAND and Oregon Health Insurance studies in the United States, which largely reported similar results.

It’s about the delta

Logos trumps pathos. Sure, my physician colleagues can tell scary anecdotes of bad outcomes caused by an inexperienced NP or PA. I would counter that by saying I have sat on our hospital’s peer review committee for 2 decades, including the era before NPs or PAs were practicing, and I have plenty of stories of physician errors. These include, of course, my own errors.

Logos: We must consider the difference between non–MD-led care and MD-led care.

My arguments from 2020 remain relevant today. Most medical problems are not engineering puzzles. Many, perhaps most, patients fall into an easy protocol – say, chest pain, dyspnea, or atrial fibrillation. With basic training, a motivated serious person quickly gains skill in recognizing and treating everyday problems.

And just 2 years on, technology further levels the playing field. Consider radiology in 2022 – it’s easy to take for granted the speed of the CT scan, the fidelity of the MRI, and the easy access to both in the U.S. hospital system. Less experienced clinicians have never had more tools to assist with diagnostics and therapeutics.

The expansion of team-based care has also mitigated the effects of inexperience. It took Americans longer than Canadians to figure out how helpful pharmacists could be. Pharmacists in my hospital now help us dose complicated medicines and protect us against prescribing errors.

Then there is the immediate access to online information. Gone are the days when you had to memorize long-QT syndromes. Book knowledge – that I spent years acquiring – now comes in seconds. The other day an NP corrected me. I asked, Are you sure? Boom, she took out her phone and showed me the evidence.

In sum, if it were even possible to measure the clinical competence of care from NP and PA versus physicians, there would be two bell-shaped curves with a tremendous amount of overlap. And that overlap would steadily increase as a given NP or PA gathered experience. (The NP in our electrophysiology division has more than 25 years’ experience in heart rhythm care, and it is common for colleagues to call her before one of us docs. Rightly so.)
 

Three basic proposals regarding NP and PA care

To ensure quality of care, I have three proposals.

It has always seemed strange to me that an NP or PA can flip from one field to another without a period of training. I can’t just change practice from electrophysiology to dermatology without doing a residency. But NPs and PAs can.

My first proposal would be that NPs and PAs spend a substantial period of training in a field before practice – a legit apprenticeship. The duration of this period is a matter of debate, but it ought to be standardized.

My second proposal is that, if physicians are required to pass certification exams, so should NPs. (PAs have an exam every 10 years.) The exam should be the same as (or very similar to) the physician exam, and it should be specific to their field of practice.

While I have argued (and still feel) that the American Board of Internal Medicine brand of certification is dubious, the fact remains that physicians must maintain proficiency in their field. Requiring NPs and PAs to do the same would help foster specialization. And while I can’t cite empirical evidence, specialization seems super-important. We have NPs at my hospital who have been in the same area for years, and they exude clinical competence.

Finally, I have come to believe that the best way for nearly any clinician to practice medicine is as part of a team. (The exception being primary care in rural areas where there are clinician shortages.)

On the matter of team care, I’ve practiced for a long time, but nearly every day I run situations by a colleague; often this person is an NP. The economist Friedrich Hayek proposed that dispersed knowledge always outpaces the wisdom of any individual. That notion pertains well to the increasing complexities and specialization of modern medical practice.

A person who commits to learning one area of medicine, enjoys helping people, asks often for help, and has the support of colleagues is set up to be a successful clinician – whether the letters after their name are APRN, PA, DO, or MD.

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky. He did not report any relevant financial disclosures. A version of this article first appeared on Medscape.com.