Cardiology

Rates of heart failure (HF) caused by methamphetamine abuse are climbing quickly in the western United States, at great financial and societal cost, suggests an analysis that documents the trends in California over a recent decade.

In the new study, methamphetamine-associated HF (meth-HF) admissions in the state rose by 585% between 2008 and 2018, and charges related those hospitalizations jumped 840%. Cases of HF unrelated to meth fell by 6% during the same period.

The recent explosion in meth-HF hospitalizations has also been costly for society in general, because most cases are younger adults in their most productive, prime earning years, Susan X. Zhao, MD, Santa Clara Valley Medical Center, San Jose, Calif., said in an interview.

“Over the past 11 years, especially since 2018, it has really started to take off, with a pretty dramatic rise. And it happened without much attention, because when we think about drugs, we think about acute overdose and not so much about the chronic, smoldering, long-term effects,” said Dr. Zhao, who is lead author on the study published July 13, 2021, in Circulation: Cardiovascular Quality and Outcomes.

“It’s really affecting a section of the population that is not supposed to be having heart failure problems. I think it is going to continue for the next decade until we put a stop to the parent problem, which is methamphetamine,” Dr. Zhao said. “We’re at the beginning, even though the rise has been pretty dramatic. The worst is yet to come.”
 

Under the radar

Methamphetamine-associated HF has been a growing problem for many years but has largely been “flying under the radar” because HF hospitalization data focus on Medicare-age patients, not the overwhelmingly younger meth-HF population, the report notes.

“We have to get this message out. Many of my patients with meth heart failure had no idea this would happen to them. They didn’t know,” Dr. Zhao said. “Once I tell them that this is what methamphetamines will do to you after years and years of use, they say they wish someone had told them.”

Dr. Zhao and colleagues looked at HF admission data collected by California’s Health and Human Services Agency to assess meth-HF trends and disease burden. They identified 1,033,076 HF hospitalizations during the decade, of which 42,565 (4.12%) were for meth-HF.

Patients hospitalized with meth-HF had a mean age of 49.6 years, compared with 72.2 for the other patients admitted with HF (P < .001). Virtually all of the patients hospitalized for meth-HF were younger than 65 years: 94.5%, compared with 30% for the other HF patients (P < .001).

Hospitalized patients with meth-HF were mostly men, their prevalence of 80% contrasting with 52.4% for patients with non–meth-related HF (P < .001).

Rates of hospitalization for meth-HF steadily increased during the study period. The age-adjusted rate of meth-HF hospitalization per 100,000 rose from 4.1 in 2008 to 28.1 in 2018. The rate of hospitalization for HF unrelated to meth actually declined, going from 342.3 in 2008 to 321.6 in 2018.

Charges for hospitalizations related to meth-HF shot up more than eight times, from $41.5 million in 2008 to $390.2 million in 2018. In contrast, charges for other HF hospitalizations rose by only 82%, from $3.5 billion to $6.3 billion.
 

Multiple layers of prevention

Dr. Zhao proposed ways that clinicians can communicate with their patients who are using or considering to use meth. “There are multiple layers of prevention. For people who are thinking of using meth, they need to get the message that something really bad can happen to them years down the road. They’re not going to die from it overnight, but it will damage the heart slowly,” she said.

The next layer of prevention can potentially help meth users who have not yet developed heart problems, Dr. Zhao said. “This would be the time to say, ‘you’re so lucky, your heart is still good. It’s time to stop because people like you, a few years from now are going to die prematurely from a very horrible, very suffering kind of death’.”

Importantly, in meth users who have already developed HF, even then it may not be too late to reverse the cardiomyopathy and symptoms. For up to a third of people with established meth-HF, “if they stop using meth, if they take good cardiac medications, and if the heart failure is in an early enough course, their heart can entirely revert to normal,” Dr. Zhao said, citing an earlier work from her and her colleagues.

Currently, methamphetamine abuse has taken especially strong root in rural areas in California and the Midwest. But Dr. Zhao predicts it will soon become prevalent throughout the United States.
 

Spotlight on an ‘epidemic’

The rapid growth of the methamphetamine “epidemic” has been well-documented in the United States and around the world, observed an accompanying editorial from Pavan Reddy, MD, Icahn School of Medicine at Mount Sinai Morningside, New York, and Uri Elkayam, MD, University of Southern California, Los Angeles.

They contend that more attention has been given to opioid overdose deaths; meth abuse does not seem to command the same attention, likely because meth is not as strongly associated with acute overdose.

But meth, wrote Dr. Reddy and Dr. Elkayam, “is a different drug with its own M.O., equally dangerous and costly to society but more insidious in nature, its effects potentially causing decades of mental and physical debilitation before ending in premature death.”

The current study “has turned a spotlight on a public health crisis that has grown unfettered for over 2 decades,” and is a call for the “medical community to recognize and manage cases of meth-HF with a comprehensive approach that addresses both mental and physical illness,” they concluded. “Only then can we hope to properly help these patients and with that, reduce the socioeconomic burden of meth-HF.”
 

A quietly building crisis

The sharp rise in meth-HF hospitalizations is an expected reflection of the methamphetamine crisis, which has been quietly building over the last few years, addiction psychiatrist Corneliu N. Stanciu, MD, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said in an interview.

“This new version of methamphetamines looks like ice and is more potent and toxic than former versions traditionally made in home-built labs,” he said. Lately the vast majority of methamphetamines in the United States have come from Mexico, are less expensive with higher purity, “and can be manufactured in greater quantities.”

Some patients with opioid use disorder (OUD) also inject methamphetamines, which can make OUD treatment clinics good places to screen for meth abuse and educate about its cardiovascular implications, Dr. Stanciu said.

“Just as addiction treatment centers present an opportunity to implement cardiac screening and referrals,” he said, “cardiology visits and hospitalizations such as those for meth-HF also present a golden opportunity for involvement of substance use disorder interventions and referrals to get patients into treatment and prevent further damage through ongoing use.”

Dr. Zhao, Dr. Reddy, Dr. Eklayam, and Dr. Stanciu report no relevant financial relationships.

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

Rates of heart failure (HF) caused by methamphetamine abuse are climbing quickly in the western United States, at great financial and societal cost, suggests an analysis that documents the trends in California over a recent decade.

In the new study, methamphetamine-associated HF (meth-HF) admissions in the state rose by 585% between 2008 and 2018, and charges related those hospitalizations jumped 840%. Cases of HF unrelated to meth fell by 6% during the same period.

The recent explosion in meth-HF hospitalizations has also been costly for society in general, because most cases are younger adults in their most productive, prime earning years, Susan X. Zhao, MD, Santa Clara Valley Medical Center, San Jose, Calif., said in an interview.

“Over the past 11 years, especially since 2018, it has really started to take off, with a pretty dramatic rise. And it happened without much attention, because when we think about drugs, we think about acute overdose and not so much about the chronic, smoldering, long-term effects,” said Dr. Zhao, who is lead author on the study published July 13, 2021, in Circulation: Cardiovascular Quality and Outcomes.

“It’s really affecting a section of the population that is not supposed to be having heart failure problems. I think it is going to continue for the next decade until we put a stop to the parent problem, which is methamphetamine,” Dr. Zhao said. “We’re at the beginning, even though the rise has been pretty dramatic. The worst is yet to come.”
 

Under the radar

Methamphetamine-associated HF has been a growing problem for many years but has largely been “flying under the radar” because HF hospitalization data focus on Medicare-age patients, not the overwhelmingly younger meth-HF population, the report notes.

“We have to get this message out. Many of my patients with meth heart failure had no idea this would happen to them. They didn’t know,” Dr. Zhao said. “Once I tell them that this is what methamphetamines will do to you after years and years of use, they say they wish someone had told them.”

Dr. Zhao and colleagues looked at HF admission data collected by California’s Health and Human Services Agency to assess meth-HF trends and disease burden. They identified 1,033,076 HF hospitalizations during the decade, of which 42,565 (4.12%) were for meth-HF.

Patients hospitalized with meth-HF had a mean age of 49.6 years, compared with 72.2 for the other patients admitted with HF (P < .001). Virtually all of the patients hospitalized for meth-HF were younger than 65 years: 94.5%, compared with 30% for the other HF patients (P < .001).

Hospitalized patients with meth-HF were mostly men, their prevalence of 80% contrasting with 52.4% for patients with non–meth-related HF (P < .001).

Rates of hospitalization for meth-HF steadily increased during the study period. The age-adjusted rate of meth-HF hospitalization per 100,000 rose from 4.1 in 2008 to 28.1 in 2018. The rate of hospitalization for HF unrelated to meth actually declined, going from 342.3 in 2008 to 321.6 in 2018.

Charges for hospitalizations related to meth-HF shot up more than eight times, from $41.5 million in 2008 to $390.2 million in 2018. In contrast, charges for other HF hospitalizations rose by only 82%, from $3.5 billion to $6.3 billion.
 

Multiple layers of prevention

Dr. Zhao proposed ways that clinicians can communicate with their patients who are using or considering to use meth. “There are multiple layers of prevention. For people who are thinking of using meth, they need to get the message that something really bad can happen to them years down the road. They’re not going to die from it overnight, but it will damage the heart slowly,” she said.

The next layer of prevention can potentially help meth users who have not yet developed heart problems, Dr. Zhao said. “This would be the time to say, ‘you’re so lucky, your heart is still good. It’s time to stop because people like you, a few years from now are going to die prematurely from a very horrible, very suffering kind of death’.”

Importantly, in meth users who have already developed HF, even then it may not be too late to reverse the cardiomyopathy and symptoms. For up to a third of people with established meth-HF, “if they stop using meth, if they take good cardiac medications, and if the heart failure is in an early enough course, their heart can entirely revert to normal,” Dr. Zhao said, citing an earlier work from her and her colleagues.

Currently, methamphetamine abuse has taken especially strong root in rural areas in California and the Midwest. But Dr. Zhao predicts it will soon become prevalent throughout the United States.
 

Spotlight on an ‘epidemic’

The rapid growth of the methamphetamine “epidemic” has been well-documented in the United States and around the world, observed an accompanying editorial from Pavan Reddy, MD, Icahn School of Medicine at Mount Sinai Morningside, New York, and Uri Elkayam, MD, University of Southern California, Los Angeles.

They contend that more attention has been given to opioid overdose deaths; meth abuse does not seem to command the same attention, likely because meth is not as strongly associated with acute overdose.

But meth, wrote Dr. Reddy and Dr. Elkayam, “is a different drug with its own M.O., equally dangerous and costly to society but more insidious in nature, its effects potentially causing decades of mental and physical debilitation before ending in premature death.”

The current study “has turned a spotlight on a public health crisis that has grown unfettered for over 2 decades,” and is a call for the “medical community to recognize and manage cases of meth-HF with a comprehensive approach that addresses both mental and physical illness,” they concluded. “Only then can we hope to properly help these patients and with that, reduce the socioeconomic burden of meth-HF.”
 

A quietly building crisis

The sharp rise in meth-HF hospitalizations is an expected reflection of the methamphetamine crisis, which has been quietly building over the last few years, addiction psychiatrist Corneliu N. Stanciu, MD, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said in an interview.

“This new version of methamphetamines looks like ice and is more potent and toxic than former versions traditionally made in home-built labs,” he said. Lately the vast majority of methamphetamines in the United States have come from Mexico, are less expensive with higher purity, “and can be manufactured in greater quantities.”

Some patients with opioid use disorder (OUD) also inject methamphetamines, which can make OUD treatment clinics good places to screen for meth abuse and educate about its cardiovascular implications, Dr. Stanciu said.

“Just as addiction treatment centers present an opportunity to implement cardiac screening and referrals,” he said, “cardiology visits and hospitalizations such as those for meth-HF also present a golden opportunity for involvement of substance use disorder interventions and referrals to get patients into treatment and prevent further damage through ongoing use.”

Dr. Zhao, Dr. Reddy, Dr. Eklayam, and Dr. Stanciu report no relevant financial relationships.

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

Rates of heart failure (HF) caused by methamphetamine abuse are climbing quickly in the western United States, at great financial and societal cost, suggests an analysis that documents the trends in California over a recent decade.

In the new study, methamphetamine-associated HF (meth-HF) admissions in the state rose by 585% between 2008 and 2018, and charges related those hospitalizations jumped 840%. Cases of HF unrelated to meth fell by 6% during the same period.

The recent explosion in meth-HF hospitalizations has also been costly for society in general, because most cases are younger adults in their most productive, prime earning years, Susan X. Zhao, MD, Santa Clara Valley Medical Center, San Jose, Calif., said in an interview.

“Over the past 11 years, especially since 2018, it has really started to take off, with a pretty dramatic rise. And it happened without much attention, because when we think about drugs, we think about acute overdose and not so much about the chronic, smoldering, long-term effects,” said Dr. Zhao, who is lead author on the study published July 13, 2021, in Circulation: Cardiovascular Quality and Outcomes.

“It’s really affecting a section of the population that is not supposed to be having heart failure problems. I think it is going to continue for the next decade until we put a stop to the parent problem, which is methamphetamine,” Dr. Zhao said. “We’re at the beginning, even though the rise has been pretty dramatic. The worst is yet to come.”
 

Under the radar

Methamphetamine-associated HF has been a growing problem for many years but has largely been “flying under the radar” because HF hospitalization data focus on Medicare-age patients, not the overwhelmingly younger meth-HF population, the report notes.

“We have to get this message out. Many of my patients with meth heart failure had no idea this would happen to them. They didn’t know,” Dr. Zhao said. “Once I tell them that this is what methamphetamines will do to you after years and years of use, they say they wish someone had told them.”

Dr. Zhao and colleagues looked at HF admission data collected by California’s Health and Human Services Agency to assess meth-HF trends and disease burden. They identified 1,033,076 HF hospitalizations during the decade, of which 42,565 (4.12%) were for meth-HF.

Patients hospitalized with meth-HF had a mean age of 49.6 years, compared with 72.2 for the other patients admitted with HF (P < .001). Virtually all of the patients hospitalized for meth-HF were younger than 65 years: 94.5%, compared with 30% for the other HF patients (P < .001).

Hospitalized patients with meth-HF were mostly men, their prevalence of 80% contrasting with 52.4% for patients with non–meth-related HF (P < .001).

Rates of hospitalization for meth-HF steadily increased during the study period. The age-adjusted rate of meth-HF hospitalization per 100,000 rose from 4.1 in 2008 to 28.1 in 2018. The rate of hospitalization for HF unrelated to meth actually declined, going from 342.3 in 2008 to 321.6 in 2018.

Charges for hospitalizations related to meth-HF shot up more than eight times, from $41.5 million in 2008 to $390.2 million in 2018. In contrast, charges for other HF hospitalizations rose by only 82%, from $3.5 billion to $6.3 billion.
 

Multiple layers of prevention

Dr. Zhao proposed ways that clinicians can communicate with their patients who are using or considering to use meth. “There are multiple layers of prevention. For people who are thinking of using meth, they need to get the message that something really bad can happen to them years down the road. They’re not going to die from it overnight, but it will damage the heart slowly,” she said.

The next layer of prevention can potentially help meth users who have not yet developed heart problems, Dr. Zhao said. “This would be the time to say, ‘you’re so lucky, your heart is still good. It’s time to stop because people like you, a few years from now are going to die prematurely from a very horrible, very suffering kind of death’.”

Importantly, in meth users who have already developed HF, even then it may not be too late to reverse the cardiomyopathy and symptoms. For up to a third of people with established meth-HF, “if they stop using meth, if they take good cardiac medications, and if the heart failure is in an early enough course, their heart can entirely revert to normal,” Dr. Zhao said, citing an earlier work from her and her colleagues.

Currently, methamphetamine abuse has taken especially strong root in rural areas in California and the Midwest. But Dr. Zhao predicts it will soon become prevalent throughout the United States.
 

Spotlight on an ‘epidemic’

The rapid growth of the methamphetamine “epidemic” has been well-documented in the United States and around the world, observed an accompanying editorial from Pavan Reddy, MD, Icahn School of Medicine at Mount Sinai Morningside, New York, and Uri Elkayam, MD, University of Southern California, Los Angeles.

They contend that more attention has been given to opioid overdose deaths; meth abuse does not seem to command the same attention, likely because meth is not as strongly associated with acute overdose.

But meth, wrote Dr. Reddy and Dr. Elkayam, “is a different drug with its own M.O., equally dangerous and costly to society but more insidious in nature, its effects potentially causing decades of mental and physical debilitation before ending in premature death.”

The current study “has turned a spotlight on a public health crisis that has grown unfettered for over 2 decades,” and is a call for the “medical community to recognize and manage cases of meth-HF with a comprehensive approach that addresses both mental and physical illness,” they concluded. “Only then can we hope to properly help these patients and with that, reduce the socioeconomic burden of meth-HF.”
 

A quietly building crisis

The sharp rise in meth-HF hospitalizations is an expected reflection of the methamphetamine crisis, which has been quietly building over the last few years, addiction psychiatrist Corneliu N. Stanciu, MD, Dartmouth-Hitchcock Medical Center, Lebanon, N.H., said in an interview.

“This new version of methamphetamines looks like ice and is more potent and toxic than former versions traditionally made in home-built labs,” he said. Lately the vast majority of methamphetamines in the United States have come from Mexico, are less expensive with higher purity, “and can be manufactured in greater quantities.”

Some patients with opioid use disorder (OUD) also inject methamphetamines, which can make OUD treatment clinics good places to screen for meth abuse and educate about its cardiovascular implications, Dr. Stanciu said.

“Just as addiction treatment centers present an opportunity to implement cardiac screening and referrals,” he said, “cardiology visits and hospitalizations such as those for meth-HF also present a golden opportunity for involvement of substance use disorder interventions and referrals to get patients into treatment and prevent further damage through ongoing use.”

Dr. Zhao, Dr. Reddy, Dr. Eklayam, and Dr. Stanciu report no relevant financial relationships.

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

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

EVIDENCE SUMMARY

Meta-analysis demonstrates accuracy of nonradiologist providers with POCUS

A systematic review and meta-­analysis (11 studies; 946 exams) compared ­nonradiologist-performed AAA screening with POCUS vs radiologist-performed aortic imaging as a gold standard. Eight trials involved emergency medicine physicians (718 exams); 1 trial, surgical residents (104 exams); 1 trial, primary care internal medicine physicians (79 exams); and 1 trial, rural family physicians (45 exams). The majority of studies were conducted in Ireland, the United Kingdom, Australia, and Canada, with 4 trials performed in the United States.¹

Researchers compared all POCUS exam findings with radiologist-performed imaging (using ultrasound, computed tomography, magnetic resonance imaging, or angiography) and with operative findings or pathology where available. There were 193 true positives, 8 false-positives, 740 true negatives, and 5 false-negatives. Primary care physicians identified 6 patients with AAA, with no false-positives or false-negatives. Overall, POCUS demonstrated a sensitivity of 0.975 (95% CI, 0.942 to 0.992) and a specificity of 0.989 (95% CI, 0.979 to 0.995).¹

Nonradiologist providers received POCUS training as follows: emergency medicine residents, 5 hours to 3 days; emergency medicine physicians, 4 to 24 hours of didactics, 50 AAA scans, or American College of Emergency Medicine certification; and primary care physicians, 2.3 hours or 50 AAA scans. Information on training for surgical residents was not supplied. The authors rated the studies for quality (10-14 points on the 14-point QUADA quality score) and heterogeneity (I² = 0 for sensitivity and I² = .38 for specificity).¹

European studies support FPs’ ability to diagnose AAA with POCUS

Two subsequent prospective diagnostic accuracy studies both found that POCUS performed by family physicians had 100% concordance with radiologist overread. The first study (in Spain) included 106 men (ages 50 and older; mean, 69 years) with chronic hypertension or a history of tobacco use. One family physician underwent training (duration not reported) by a radiologist, including experience measuring standard cross-­sections of the aorta. Radiologists reviewed all POCUS images, which identified 6 patients with AAA (confirmed by CT scan). The concordance between the family ­physician and the radiologists was absolute (kappa = 1.0; sensitivity and specificity, 100%; positive and negative predictive values, both 1.0).²

The second study (in Denmark) compared 29 POCUS screenings for AAA performed by 5 family physicians vs a gold standard of a radiologist-performed abdominal ultrasound blinded to previous ultrasound findings. Four of the family physicians were board certified and 1 was a final-year resident in training. They all underwent a 3-day ultrasonography course that included initial e-learning followed by 2 days of hands-on training; all passed a final certification exam. The family physicians identified 1 patient with AAA. Radiologists overread all the scans and found 100% agreement with the 1 positive AAA and the 28 negative scans.³

Recommendations from others

In 2019, the US Preventive Services Task Force (USPSTF) offered a Grade “B” (moderate net benefit) recommendation for screening with ultrasonography for AAA in men ages 65 to 75 years who have ever smoked, and a Grade “C” recommendation (small net benefit) for screening men ages 65 to 75 years who have never smoked.⁴ In 2017, the Canadian Task Force on Preventive Health Care recommended screening all men ages 65 to 80 years with 1 ultrasound exam for AAA (weak recommendation; moderate-quality evidence). The Canadian Task Force also noted that, with adequate training, AAA screening could be performed in a family practice setting.⁵

Editor’s takeaway

While these studies evaluating POCUS performed by nonradiologists included a small number of family physicians, their finding that all participants (attending physicians and residents) demonstrate high sensitivity and specificity for AAA detection with relatively limited training bodes well for more widespread use of the technology. Offering POCUS to detect AAAs in family physician offices has the potential to dramatically improve access to USPSTF-recommended screening.

EVIDENCE SUMMARY

Meta-analysis demonstrates accuracy of nonradiologist providers with POCUS

A systematic review and meta-­analysis (11 studies; 946 exams) compared ­nonradiologist-performed AAA screening with POCUS vs radiologist-performed aortic imaging as a gold standard. Eight trials involved emergency medicine physicians (718 exams); 1 trial, surgical residents (104 exams); 1 trial, primary care internal medicine physicians (79 exams); and 1 trial, rural family physicians (45 exams). The majority of studies were conducted in Ireland, the United Kingdom, Australia, and Canada, with 4 trials performed in the United States.¹

Researchers compared all POCUS exam findings with radiologist-performed imaging (using ultrasound, computed tomography, magnetic resonance imaging, or angiography) and with operative findings or pathology where available. There were 193 true positives, 8 false-positives, 740 true negatives, and 5 false-negatives. Primary care physicians identified 6 patients with AAA, with no false-positives or false-negatives. Overall, POCUS demonstrated a sensitivity of 0.975 (95% CI, 0.942 to 0.992) and a specificity of 0.989 (95% CI, 0.979 to 0.995).¹

Nonradiologist providers received POCUS training as follows: emergency medicine residents, 5 hours to 3 days; emergency medicine physicians, 4 to 24 hours of didactics, 50 AAA scans, or American College of Emergency Medicine certification; and primary care physicians, 2.3 hours or 50 AAA scans. Information on training for surgical residents was not supplied. The authors rated the studies for quality (10-14 points on the 14-point QUADA quality score) and heterogeneity (I² = 0 for sensitivity and I² = .38 for specificity).¹

European studies support FPs’ ability to diagnose AAA with POCUS

Two subsequent prospective diagnostic accuracy studies both found that POCUS performed by family physicians had 100% concordance with radiologist overread. The first study (in Spain) included 106 men (ages 50 and older; mean, 69 years) with chronic hypertension or a history of tobacco use. One family physician underwent training (duration not reported) by a radiologist, including experience measuring standard cross-­sections of the aorta. Radiologists reviewed all POCUS images, which identified 6 patients with AAA (confirmed by CT scan). The concordance between the family ­physician and the radiologists was absolute (kappa = 1.0; sensitivity and specificity, 100%; positive and negative predictive values, both 1.0).²

The second study (in Denmark) compared 29 POCUS screenings for AAA performed by 5 family physicians vs a gold standard of a radiologist-performed abdominal ultrasound blinded to previous ultrasound findings. Four of the family physicians were board certified and 1 was a final-year resident in training. They all underwent a 3-day ultrasonography course that included initial e-learning followed by 2 days of hands-on training; all passed a final certification exam. The family physicians identified 1 patient with AAA. Radiologists overread all the scans and found 100% agreement with the 1 positive AAA and the 28 negative scans.³

Recommendations from others

In 2019, the US Preventive Services Task Force (USPSTF) offered a Grade “B” (moderate net benefit) recommendation for screening with ultrasonography for AAA in men ages 65 to 75 years who have ever smoked, and a Grade “C” recommendation (small net benefit) for screening men ages 65 to 75 years who have never smoked.⁴ In 2017, the Canadian Task Force on Preventive Health Care recommended screening all men ages 65 to 80 years with 1 ultrasound exam for AAA (weak recommendation; moderate-quality evidence). The Canadian Task Force also noted that, with adequate training, AAA screening could be performed in a family practice setting.⁵

Editor’s takeaway

While these studies evaluating POCUS performed by nonradiologists included a small number of family physicians, their finding that all participants (attending physicians and residents) demonstrate high sensitivity and specificity for AAA detection with relatively limited training bodes well for more widespread use of the technology. Offering POCUS to detect AAAs in family physician offices has the potential to dramatically improve access to USPSTF-recommended screening.

EVIDENCE SUMMARY

Meta-analysis demonstrates accuracy of nonradiologist providers with POCUS

A systematic review and meta-­analysis (11 studies; 946 exams) compared ­nonradiologist-performed AAA screening with POCUS vs radiologist-performed aortic imaging as a gold standard. Eight trials involved emergency medicine physicians (718 exams); 1 trial, surgical residents (104 exams); 1 trial, primary care internal medicine physicians (79 exams); and 1 trial, rural family physicians (45 exams). The majority of studies were conducted in Ireland, the United Kingdom, Australia, and Canada, with 4 trials performed in the United States.¹

Researchers compared all POCUS exam findings with radiologist-performed imaging (using ultrasound, computed tomography, magnetic resonance imaging, or angiography) and with operative findings or pathology where available. There were 193 true positives, 8 false-positives, 740 true negatives, and 5 false-negatives. Primary care physicians identified 6 patients with AAA, with no false-positives or false-negatives. Overall, POCUS demonstrated a sensitivity of 0.975 (95% CI, 0.942 to 0.992) and a specificity of 0.989 (95% CI, 0.979 to 0.995).¹

Nonradiologist providers received POCUS training as follows: emergency medicine residents, 5 hours to 3 days; emergency medicine physicians, 4 to 24 hours of didactics, 50 AAA scans, or American College of Emergency Medicine certification; and primary care physicians, 2.3 hours or 50 AAA scans. Information on training for surgical residents was not supplied. The authors rated the studies for quality (10-14 points on the 14-point QUADA quality score) and heterogeneity (I² = 0 for sensitivity and I² = .38 for specificity).¹

European studies support FPs’ ability to diagnose AAA with POCUS

Two subsequent prospective diagnostic accuracy studies both found that POCUS performed by family physicians had 100% concordance with radiologist overread. The first study (in Spain) included 106 men (ages 50 and older; mean, 69 years) with chronic hypertension or a history of tobacco use. One family physician underwent training (duration not reported) by a radiologist, including experience measuring standard cross-­sections of the aorta. Radiologists reviewed all POCUS images, which identified 6 patients with AAA (confirmed by CT scan). The concordance between the family ­physician and the radiologists was absolute (kappa = 1.0; sensitivity and specificity, 100%; positive and negative predictive values, both 1.0).²

The second study (in Denmark) compared 29 POCUS screenings for AAA performed by 5 family physicians vs a gold standard of a radiologist-performed abdominal ultrasound blinded to previous ultrasound findings. Four of the family physicians were board certified and 1 was a final-year resident in training. They all underwent a 3-day ultrasonography course that included initial e-learning followed by 2 days of hands-on training; all passed a final certification exam. The family physicians identified 1 patient with AAA. Radiologists overread all the scans and found 100% agreement with the 1 positive AAA and the 28 negative scans.³

Recommendations from others

In 2019, the US Preventive Services Task Force (USPSTF) offered a Grade “B” (moderate net benefit) recommendation for screening with ultrasonography for AAA in men ages 65 to 75 years who have ever smoked, and a Grade “C” recommendation (small net benefit) for screening men ages 65 to 75 years who have never smoked.⁴ In 2017, the Canadian Task Force on Preventive Health Care recommended screening all men ages 65 to 80 years with 1 ultrasound exam for AAA (weak recommendation; moderate-quality evidence). The Canadian Task Force also noted that, with adequate training, AAA screening could be performed in a family practice setting.⁵

Editor’s takeaway

While these studies evaluating POCUS performed by nonradiologists included a small number of family physicians, their finding that all participants (attending physicians and residents) demonstrate high sensitivity and specificity for AAA detection with relatively limited training bodes well for more widespread use of the technology. Offering POCUS to detect AAAs in family physician offices has the potential to dramatically improve access to USPSTF-recommended screening.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

Five risk factors might help pinpoint patients at risk of developing device-related thrombus (DRT), itself an important risk factor for cerebrovascular events, in patients with implants for left atrial appendage occlusion (LAAO), new research suggests.

The identified independent predictors of DRT in the largest dedicated multicenter LAAO-DRT registry to date were presence of a hypercoagulability disorder, pericardial effusion, renal insufficiency, an implantation depth greater than 10 mm from the pulmonary ridge, and presence of nonparoxysmal atrial fibrillation (AFib).

“Unfortunately, most of them are not modifiable, like hypercoaguable disorders or nonparoxysmal atrial fibrillation. But we can avoid deep implants because that’s been associated with creating a little bit of a crater or valley where the clot can form,” senior author Mohamad Alkhouli, MD, said in an interview.

But most important, and “really why we wanted to do this,” he said, is that “we want to give the patient a realistic prediction of adverse events for this procedure.”

LAAO has taken off in recent years for preventing thrombus formation and stroke in patients with AFib. Predicting DRT is a priority for the LAAO field, the authors note, especially given its expansion to younger, lower-risk patients and the increasing procedural volumes.

“This is a problem, DRT, that’s been discussed a lot because this is a preventative procedure,” observed Dr. Alkhouli, professor of medicine at Mayo Medical School, Rochester, Minn.

“The actual stroke risk every year – even if you don’t take any blood thinner and you have a CHADsVASc score of 9, the highest – is 11%. So if the chance of having thrombus is close, then that’s not a good tradeoff.”

Previous studies have also identified implantation depth and nonparoxysmal AFib as risk factors for DRT. But most of them have been small, he noted, with one of the largest reporting 65 DRTs in four prospective trials.

To cast a wider net, the investigators, led by Trevor Simard, MD, also from the Mayo Clinic, invited more than 50 international sites to contribute data to the registry. Of these, 37 centers reported on 237 DRTs and 474 device-matched control subjects from the same site.

Three-fourths of patients received a first-generation Watchman or a FLEX device (Boston Scientific).

Medical regimens were similar between the DRT and control cohorts at discharge after LAA closure. Most patients were managed with single (36.3%) or dual antiplatelet therapy (26.2%) at the time of DRT diagnosis.

As reported July 19 in the Journal of the American College of Cardiology, the timing of DRT development varied widely, with 24.9% appearing in the first 45 days, 38.8% between days 45 and 180, 16.0% between days 180 to 365, and 20.3% beyond 1 year. At last known follow-up, one-quarter of patients had DRT.

The odds ratios for DRT associated with the five identified risk factors were:

• 17.50 (95% confidence interval, 3.39-90.45) for hypercoagulability disorder
• 13.45 (95% CI, 1.46-123.52) for pericardial effusion
• 4.02 (95% CI, 1.22-13.25) for renal insufficiency
• 2.41 (95% CI, 1.57-3.69) for implantation depth >10 mm
• 1.90 (95% CI, 1.22-2.97) for nonparoxysmal AFib

The risk for a composite of death, ischemic stroke, and systemic embolization was twofold higher in the DRT cohort than in the control cohort (29.5% vs. 14.4%; hazard ratio, 2.37; 95% CI, 1.58-3.56) and driven by a higher rate of ischemic stroke (16.9% vs. 3.6%; HR, 3.49; 95% CI, 1.35-9.00).

The incidence of bleeding and intracerebral hemorrhage, however, was similar in the DRT and control cohorts.

One of the surprises of the study was that medications prescribed in the short term after LAA closure were not associated with DRT, Dr. Alkhouli said. A previous meta-analysis of 66 studies by the investigators also found that antithrombotic regimen did not explain the heterogeneity of DRT formation.

“I think we’ll have to take that with a grain of salt, because there’s so many variations in the practice, and this is observational data. But that, in my mind, brings up a mechanistic issue,” he said.

It’s often recommended “that we should put patients on blood thinners for 3 months or 6 weeks, or whatever it is, to decrease the chance of thrombus, assuming the patients will have a normal endothelialization of the device,” Dr. Alkhouli said.

“Well, we know that’s not the reality,” he continued. “We know many patients don’t endothelialize, and, even if some patients do, there may be some endothelial damage. So I think the whole mechanism of prescribing a little bit of a blood thinner to avoid that risk may be missing the point. It’s a bit more complex than that, evidenced also by the fact that three-fourths of all the DRTs happened after 45 days, when patients are typically not taking a blood thinner.”

Based on the five independent risk factors, the investigators created a clinical DRT risk score that assigned 1 point for renal insufficiency, implantation depth greater than 10 mm from the pulmonary ridge, and nonparoxysmal AFib; and 4 points for iatrogenic pericardial effusion and for hypercoagulability disorder. Low risk was categorized as 1 point and high risk as 2 or more points.

The presence of one major risk factor or two minor risk factors, for example, led to a 2.1-fold increased risk for DRT, compared with those with no DRT risk factors.

The risk score will require validation in a prospective cohort but is “a step forward in addressing DRT” and triaging patients, Dr. Alkhouli said. The findings highlight the need to avoid deep device implantation and the importance of shared decision-making with patients, especially with those at high risk.

“And third, which is most important, I think, in my mind, is that it tells us not to put a blind eye to this topic and just say with improved devices it will go away,” he said. “That’s a bit unrealistic.”

In an accompanying editorial, Oussama Wazni, MD, Walid Saliba, MD, and Ayman A. Hussein, MD, all from the Cleveland Clinic, write that “the study sheds light on this yet unresolved issue, and the observations may help with risk stratification and optimization of procedural techniques.”

Whereas many of the nonmodifiable risk factors are helpful in shared decision-making decisions, they continue, “knowledge of these risk factors may not preclude implantation in patients who are otherwise at risk of both stroke off anticoagulation and bleeding on anticoagulation.”

Dr. Wazni and colleagues acknowledge that the small number of events in the study limits statistical power for definitive conclusions and say that further studies are needed to clarify the natural history of DRTs and their management, resolution, and impact on cardiovascular events.

Practitioners should also continue to cautiously assess for LAAO clinical indications for implant, according to the editorialists, who point out that the regulatory approval language in the United States was “flexible and nonspecific.”

“As the field grows wider, enhancing LAAO safety with optimal design, implantation, and periprocedural management is critically important, yet the main focus should remain on optimal patient selection for the purpose of achieving safe and successful outcomes,” the editorialists conclude.

Dr. Alkhouli has served as a consultant for Boston Scientific. Coauthor disclosures are listed in the paper. Dr. Wazni and Dr. Hussein have received research grant support from Boston Scientific. Dr. Wazni and Dr. Saliba have been consultants for Boston Scientific.

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

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

In patients with intermediate risk of atherosclerotic cardiovascular disease along with risk-enhancing factors, coronary artery calcium scoring may help more precisely calculate their need for statin therapy.

Furthermore, when the need for statin treatment isn’t so clear and patients need additional risk assessment, the scoring can provide further information to personalize clinical decision making, according to a cross-sectional study of 1,688 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) published in JAMA Cardiology.

And regardless of coronary artery calcium (CAC), a low ankle brachial index (ABI) score is a marker for statin therapy, the study found.

The study looked at CAC scoring in the context of ABI and other risk-enhancing factors identified in the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines: a family history of premature atherosclerotic cardiovascular disease (ASCVD), lipid and inflammatory biomarkers, chronic kidney disease, chronic inflammatory conditions, premature menopause or preeclampsia, and South Asian ancestry.

Any number of these factors can indicate the need for statins in people with borderline or intermediate risk. The guidelines also call for selective use of CAC to aid the decision-making process for statin therapy when the risk for developing atherosclerosis isn’t so clear.

“The novel risk-enhancing factors are not perfect,” said lead author Jaideep Patel, MD, director of preventive cardiology at Johns Hopkins Heart Center at Greater Baltimore Medical Center. He noted that the 2018 dyslipidemia guidelines suggested the risk for cardiovascular events rises when new risk-enhancing factors emerge, and that it was difficult to predict the extent to which each enhancer could change the 10-year risk. 
 

Utility of CAC

“In this setting, the most significant finding that supports the utility of CAC scoring is when CAC is absent – a CAC of 0 – even in the setting of any of these enhancers, whether it be single or multiple, the 10-year risk remains extremely low – at the very least below the accepted threshold to initiate statin therapy,” Dr. Patel said.

That threshold is below the 7.5% 10-year ASCVD incidence rate. Over the 12-year mean study follow-up, the ASCVD incidence rate among patients with a CAC score of 0 for all risk-enhancing factors was 7.5 events per 1,000 person years, with one exception: ABI had an incidence rate of 10.4 events per 1,000 person years. “A low ABI score should trigger statin initiation irrespective of CAC score,” Dr. Patel said.

The study found a CAC score of 0 in 45.7% of those with one or two risk-enhancing factors versus 40.3% in those with three or more. “Across all the risk enhancers (except low ABI), the prevalence of CAC of 0 was greater than 50% in women; that is, enhancers overestimate risk,” Dr. Patel said. “The prevalence of CAC of 0 was approximately 40% across all risk enhancers; that is, enhancers overestimate risk.”

Dr. Patel said previous studies have suggested the risk of a major cardiovascular event was almost identical for statin and nonstatin users with a CAC score of 0. “If there is uncertainty about statin use after the physician-patient risk discussion,” he said, “CAC scoring may be helpful to guide the use of statin therapy.”

Senior author Mahmoud Al Rifai, MD, MPH, added: “For example, if CAC was absent, a statin could be deprescribed if there’s disutility on the part of the patient, with ongoing lifestyle and risk factor modification efforts.” Dr. Al Rifai is a cardiology fellow at Baylor College of Medicine, Houston.

Dr. Patel said: “Alternatively, if CAC was present, then it would be prudent to continue statin therapy.”

While South Asian ethnicity is a risk enhancing factor, the investigators acknowledged that MESA didn’t recruit this population group.
 

Study confirms guidelines

The study “supports the contention of the [AHA/ACC] guidelines that, in people who are in this intermediate risk range, there may be factors that either favor statin treatment or suggest that statin treatment could be deferred,” said Neil J. Stone, MD, of Northwestern University, Chicago, and author of the 2013 ASCVD risk calculator. “The guidelines pointed out that risk-enhancing factors may be associated with an increase in lifetime risk, not necessarily short term, and so could inform a more personalized risk discussion.”

The study findings validate the utility of CAC for guiding statin therapy, Dr. Stone said. “For those who have felt that a calcium score is not useful,” he said, “this is additional evidence to show that, in the context of making a decision in those at intermediate risk as proposed by the guidelines, a calcium score is indeed very useful.”

Dr. Stone added: “An important clinical point not mentioned by the authors is that, when the patient has a CAC score of 0 and risk factors, this may be exactly the time to be aggressive with lifestyle to prevent them from developing a positive CAC score and atherosclerosis, because once atherosclerosis is present, treatment may not restore the risk back to the original lower state.”

Dr. Patel, Dr. Al Rifai, and Dr. Stone have no relevant relationships to disclose. A number of study coauthors disclosed multiple financial relationships.

The U.S. Food and Drug Administration (FDA) aims to update the labeling on all statins to remove the drugs’ blanket contraindication in all pregnant patients, the agency has announced. The change should reinforce for both physicians and patients that statin use in women with unrecognized pregnancy is unlikely to be harmful, it said.

“Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.”

The revision should emphasize for clinicians “that statins are safe to prescribe in patients who can become pregnant and help them reassure patients with unintended statin exposure in early pregnancy,” the FDA explained.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke." That includes women with homozygous familial hypercholesterolemia and those who are prescribed statins for secondary prevention, the agency said.

Clinicians “should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy. Because of the chronic nature of cardiovascular disease, treatment of hyperlipidemia is not generally necessary during pregnancy.”

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

The U.S. Food and Drug Administration (FDA) aims to update the labeling on all statins to remove the drugs’ blanket contraindication in all pregnant patients, the agency has announced. The change should reinforce for both physicians and patients that statin use in women with unrecognized pregnancy is unlikely to be harmful, it said.

“Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.”

The revision should emphasize for clinicians “that statins are safe to prescribe in patients who can become pregnant and help them reassure patients with unintended statin exposure in early pregnancy,” the FDA explained.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke." That includes women with homozygous familial hypercholesterolemia and those who are prescribed statins for secondary prevention, the agency said.

Clinicians “should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy. Because of the chronic nature of cardiovascular disease, treatment of hyperlipidemia is not generally necessary during pregnancy.”

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

The U.S. Food and Drug Administration (FDA) aims to update the labeling on all statins to remove the drugs’ blanket contraindication in all pregnant patients, the agency has announced. The change should reinforce for both physicians and patients that statin use in women with unrecognized pregnancy is unlikely to be harmful, it said.

“Because the benefits of statins may include prevention of serious or potentially fatal events in a small group of very high-risk pregnant patients, contraindicating these drugs in all pregnant women is not appropriate.”

The revision should emphasize for clinicians “that statins are safe to prescribe in patients who can become pregnant and help them reassure patients with unintended statin exposure in early pregnancy,” the FDA explained.

Removal of the broadly worded contraindication should “enable health care professionals and patients to make individual decisions about benefit and risk, especially for those at very high risk of heart attack or stroke." That includes women with homozygous familial hypercholesterolemia and those who are prescribed statins for secondary prevention, the agency said.

Clinicians “should discontinue statin therapy in most pregnant patients, or they can consider the ongoing therapeutic needs of the individual patient, particularly those at very high risk for cardiovascular events during pregnancy. Because of the chronic nature of cardiovascular disease, treatment of hyperlipidemia is not generally necessary during pregnancy.”

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

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Background: Atrial fibrillation (Afib) is the most common arrhythmia requiring treatment in the ED. There is a paucity of literature regarding the management of acute (onset < 48 h) atrial fibrillation in this setting and no conclusive evidence exists regarding the superiority of pharmacologic vs. electrical cardioversion.

The “drug-shock” group achieved and maintained sinus rhythm in 96% of cases, compared to 92% in the “placebo-shock” group (statistically insignificant difference). The procainamide infusion alone achieved and maintained sinus rhythm in 52% of recipients, who thereby avoided the need for procedural sedation and monitoring. Notably, only 2% of patients in the study required admission to the hospital. Pad placement was equally efficacious in the AL or AP positions. The most common adverse event observed was transient hypotension during infusion of procainamide. No strokes were observed in either arm. Follow-up ECGs obtained 14 days later showed that 95% of patients remained in sinus rhythm.

Bottom line: Pharmacologic cardioversion with procainamide infusion and/or electrical cardioversion is a safe and efficacious initial management strategy for acute atrial fibrillation, and all but eliminates the need for hospital admission.

Citation: Stiell IG et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomized trial. Lancet. 2020 Feb 1;395(10221):339-49.

Dr. Lawson is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.

Background: Atrial fibrillation (Afib) is the most common arrhythmia requiring treatment in the ED. There is a paucity of literature regarding the management of acute (onset < 48 h) atrial fibrillation in this setting and no conclusive evidence exists regarding the superiority of pharmacologic vs. electrical cardioversion.

The “drug-shock” group achieved and maintained sinus rhythm in 96% of cases, compared to 92% in the “placebo-shock” group (statistically insignificant difference). The procainamide infusion alone achieved and maintained sinus rhythm in 52% of recipients, who thereby avoided the need for procedural sedation and monitoring. Notably, only 2% of patients in the study required admission to the hospital. Pad placement was equally efficacious in the AL or AP positions. The most common adverse event observed was transient hypotension during infusion of procainamide. No strokes were observed in either arm. Follow-up ECGs obtained 14 days later showed that 95% of patients remained in sinus rhythm.

Bottom line: Pharmacologic cardioversion with procainamide infusion and/or electrical cardioversion is a safe and efficacious initial management strategy for acute atrial fibrillation, and all but eliminates the need for hospital admission.

Citation: Stiell IG et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomized trial. Lancet. 2020 Feb 1;395(10221):339-49.

Dr. Lawson is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.

Background: Atrial fibrillation (Afib) is the most common arrhythmia requiring treatment in the ED. There is a paucity of literature regarding the management of acute (onset < 48 h) atrial fibrillation in this setting and no conclusive evidence exists regarding the superiority of pharmacologic vs. electrical cardioversion.

The “drug-shock” group achieved and maintained sinus rhythm in 96% of cases, compared to 92% in the “placebo-shock” group (statistically insignificant difference). The procainamide infusion alone achieved and maintained sinus rhythm in 52% of recipients, who thereby avoided the need for procedural sedation and monitoring. Notably, only 2% of patients in the study required admission to the hospital. Pad placement was equally efficacious in the AL or AP positions. The most common adverse event observed was transient hypotension during infusion of procainamide. No strokes were observed in either arm. Follow-up ECGs obtained 14 days later showed that 95% of patients remained in sinus rhythm.

Bottom line: Pharmacologic cardioversion with procainamide infusion and/or electrical cardioversion is a safe and efficacious initial management strategy for acute atrial fibrillation, and all but eliminates the need for hospital admission.

Citation: Stiell IG et al. Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomized trial. Lancet. 2020 Feb 1;395(10221):339-49.

Dr. Lawson is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.