Cardiology News

Results of the REDUCE-IT trial suggested that icosapent ethyl lowers the risk for ischemic events among patients with high triglycerides despite statin use – but immediately, controversy swirled.

The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.

However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
 

‘Not all omega-3s created equal’

Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”

REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.

Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”

The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”

Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.

More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
 

Placebo effects?

Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.

Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”

“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.

“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”

“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
 

Still room for benefit?

Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.

Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”

Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”

Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”

“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”

Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.

Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”

“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
 

Clinical inertia?

Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”

Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”

“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”

Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.

Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.

Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”

Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”

Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”

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

Results of the REDUCE-IT trial suggested that icosapent ethyl lowers the risk for ischemic events among patients with high triglycerides despite statin use – but immediately, controversy swirled.

The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.

However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
 

‘Not all omega-3s created equal’

Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”

REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.

Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”

The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”

Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.

More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
 

Placebo effects?

Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.

Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”

“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.

“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”

“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
 

Still room for benefit?

Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.

Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”

Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”

Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”

“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”

Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.

Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”

“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
 

Clinical inertia?

Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”

Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”

“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”

Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.

Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.

Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”

Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”

Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”

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

Results of the REDUCE-IT trial suggested that icosapent ethyl lowers the risk for ischemic events among patients with high triglycerides despite statin use – but immediately, controversy swirled.

The prescription product (Vascepa), consisting of a “highly purified” form of the omega-3 acid eicosapentaenoic acid (EPA), was heralded in 2018 (N Engl J Med. 2019;380:11-22) as ushering in “the dawn of a new era” in cardiovascular disease (CVD) prevention that “should definitely change practice going forward,” according to REDUCE-IT’s lead author Deepak L. Bhatt, MD, formerly of Brigham and Women’s Hospital in Boston and now director of the Mount Sinai Heart Center in New York.

However, skeptics questioned why the results differed from most previous trials of fish oil that showed no benefit. Was it caused by the high dose of EPA: 4 g/daily versus 1 g daily in earlier trials with fish oil capsules? Was it the different formulation of purified EPA versus more common combinations of EPA plus docosahexaenoic acid (DHA)? Or, as suggested by Steven Nissen, MD, chief academic officer of Cleveland Clinic’s Heart and Vascular Institute and others, was it caused by the negative effects of the mineral oil placebo, given the significant increases in LDL cholesterol and high-sensitivity C-reactive protein (hsCRP) seen in the control group?
 

‘Not all omega-3s created equal’

Dr. Bhatt recently said in an interview: “I think there’s confusion in the field. It’s a challenge when just one drug in a class looks good and everything else in that class looks bad. That in itself can breed some skepticism. Also, not everyone always embraces advances. Some people have other reasons to impugn datasets; for example, it could be because they are running competing trials with competing drugs.”

REDUCE-IT enrolled more than 8,000 patients at high CV risk despite statin treatment, and randomly assigned them to 2 g of EPA twice daily or the mineral oil placebo. Although the results showed a 25% reduction in the rate of CV events in the EPA group, there was also an increased risk of atrial fibrillation among those taking EPA after a median of 4.9 years follow-up.

Dr. Bhatt noted that Amarin, which manufactures Vascepa, is essentially a one-drug company, and its stock price is dependent on the product. When the trial results were released, he said, “there were people in the investor world that wanted the stock price to go up or wanted it to go down, and they were alternately hyping or disparaging the data in both cases, sometimes inappropriately and excessively, which created noise around the science.”

The fact is, he said, “not all omega-3 fatty acids are created equal. There are differences between supplements and prescription medicines, and within the prescription medicines, differences between pure EPA and the mixtures of EPA and DHA.”

Dr. Bhatt added that other trials also showed positive results. He pointed to the JELIS trial, published in 2007, which showed a 19% reduction in major adverse CV events with a 1.8-g daily EPA dose.

More recently, RESPECT-EPA was presented at the 2022 annual meeting of the American Heart Association. That study had methodological issues and was underpowered, but it did suggest a possible benefit of EPA in reducing CV events in patients with chronic coronary artery disease who were taking statins. “Looking at the totality of evidence, I think it’s quite clear there’s CV benefit,” Dr. Bhatt said.
 

Placebo effects?

Concerns about the mineral oil placebo cast doubt on that benefit. Table 4 of the supplement accompanying REDUCE-IT’s publication in the New England Journal of Medicine shows significant increases of non–HDL cholesterol, LDL cholesterol, apolipoprotein B, and hsCRP in the control group.

Jane Armitage, MBBS, a professor of clinical trials and epidemiology, clinical trial service unit at Oxford University (England), said in an interview: “I was surprised by the backlash and at the time felt that it was unlikely that the mineral oil was the problem. But the size of benefit was still out of kilter.”

“Two further pieces of evidence have influenced my thoughts since then,” she said. One is the lack of effect of high doses of fish oils in the STRENGTH trial. STRENGTH tested 4 g of omega-3 oil containing a mixture of EPA and DHA and found no benefit in statin-treated, high-risk patients.

“The amount of EPA [was] substantially less than given in REDUCE-IT,” Armitage said, “but it seems to me that in a similar hypertriglyceridemic population, if the effect were due to the EPA, you would have seen some impact in STRENGTH – and none was seen.”

“The other piece of evidence is in a paper by Paul Ridker, MD, et al. on the changes in biomarkers during REDUCE-IT,” she said. “Several inflammatory biomarkers associated with atherosclerosis rose during the study among those allocated mineral oil, but remained largely unchanged in the EPA group. This is in contrast to what is seen with these biomarkers in other large trials, where no changes were seen in the placebo groups, and once again raises the possibility that the apparent benefits of EPA may be related to hazard from the mineral oil.”
 

Still room for benefit?

Based largely on the results of REDUCE-IT, Vascepa is currently approved by the Food and Drug Administration as an adjunctive therapy to lower the risk for CV events among adults with elevated triglyceride levels (≥ 150 mg/dL). Patients must also have either established CVD or diabetes and two or more additional CV risk factors and are advised to continue physical activity and maintain a healthy diet.

Dr. Nissen, the principal author of the STRENGTH trial, said in an interview, “REDUCE-IT is an outlier. Other trials of omega-3 fatty acids, some of them very large, showed no benefits, and a meta-analysis of nearly 78,000 patients showed no beneficial effects. In this context,” he said, “the large ‘benefit’ observed in REDUCE-IT doesn’t make any sense.”

Dr. Nissen noted that a secondary analysis of STRENGTH further showed that higher plasma EPA levels did not reduce CV outcomes. He also highlighted the elevated risk of atrial fibrillation with EPA. “We need to see another study comparing EPA to a neutral comparator such as corn oil, which had no significant effect on lipid or inflammatory biomarkers in STRENGTH,” he said. “Without such a trial, the results of REDUCE-IT cannot be accepted as definitive.”

Dr. Ridker, the lead author of the REDUCE-IT substudy that found biomarker changes with the mineral oil placebo, said in an interview: “Is it possible that EPA is an outstanding drug? Absolutely, and I continue to think it useful for our very high-risk, secondary-prevention patients when we are running out of options.”

“But,” said Dr. Ridker, who is a professor at Harvard Medical School, Boston, and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s, “the reality ... is that ongoing uncertainties need resolution.” Like Dr. Nissen, he thinks the best way to resolve these uncertainties is through a second trial using a fully neutral comparator. “I am hopeful that the U.S. National Institutes of Health will see fit to undertake such an endeavor, perhaps with support from industry partners.”

Although Dr. Armitage is no longer in clinical practice, when asked how she might use EPA, she said it might be reasonable for patients who meet the prescribing criteria and remain high risk after all other risk factors have been addressed. She added that, although EPA is approved in the United Kingdom, she doesn’t think it is being widely prescribed.

Salim S. Virani, MD, PhD, a professor in the Sections of Cardiology and Cardiovascular Research at Baylor College of Medicine who has published articles about REDUCE-IT and on the eligibility and cost of EPA in the Veterans Affairs system, said in an interview: “In my personal opinion, clinicians [should] first optimize diet and lifestyle and work on secondary causes, as they play a very big role in hypertriglyceridemia.” He also recommended optimizing LDL-C levels because of “consistent data showing that LDL [cholesterol] control leads to significant reduction in atherosclerotic CVD events.”

“Once these two steps are taken and triglycerides still remain elevated,” he said, “then adding EPA in patients with established atherosclerotic CVD or those with diabetes plus other CV risk factors may be a reasonable option to further lower residual atherosclerotic CVD risk.”
 

Clinical inertia?

Dr. Bhatt acknowledged that, despite the benefit of EPA in the context of REDUCE-IT, “a few issues stand in the way of prescribing, particularly in the U.S.”

Vascepa’s manufacturer Amarin lost a patent challenge in the United States, enabling the relatively early introduction of multiple generics. “They’ve lost interest in the U.S. because there are three generics.”

“The sad truth is, if there isn’t a drug rep saying, ‘hey, look at this new data,’ there’s clinical inertia,” said Dr. Bhatt. He believes that the lack of marketing will hurt awareness among physicians and “ultimately hurt patients because they won’t get the drug.”

Cost is also an issue, Dr. Bhatt affirmed. Vascepa has significant out-of-pocket costs for many patients, as do some of the generics. Currently, the branded product costs about $300 per month without insurance, according to drugs.com; prices for generics vary widely, running anywhere from $82 to $200 or more.

Despite these challenges, he noted that many guidelines around the world have already changed to reflect the data, including the American Diabetes Association and the U.S. National Lipid Association.

Will there be another trial of EPA with a neutral placebo? Dr. Bhatt believes it’s not going to happen. “The company that funded REDUCE-IT is struggling just to stay alive, and another investigator-funded trial like RESPECT EPA would probably be underpowered and not move the needle much.”

Dr. Virani agreed that while it would be best to test EPA against a fully inert placebo, “whether there is enough appetite to fund such a large trial remains a big question.”

Meanwhile, Dr. Bhatt said, “EPA is not for everybody, but for the high-risk patients who meet the stringent inclusion criteria of REDUCE-IT, I think clinicians should at least consider use of EPA in a way consistent with the U.S. FDA label, the Canadian label, and the label in parts of Europe where the drug is being introduced.”

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

The ‘scheme’ in the name should have been a clue

Retirement. The shiny reward to a lifetime’s worth of working and saving. We’re all literally working to get there, some of us more to get there early, but current research reveals that early retirement isn’t the relaxing finish line we dream about, cognitively speaking.

FatCamera/Getty Images

Researchers at Binghamton (N.Y.) University set out to examine just how retirement plans affect cognitive performance. They started off with China’s New Rural Pension Scheme (scheme probably has a less negative connotation in Chinese), a plan that financially aids the growing rural retirement-age population in the country. Then they looked at data from the Chinese Health and Retirement Longitudinal Survey, which tests cognition with a focus on episodic memory and parts of intact mental status.

What they found was the opposite of what you would expect out of retirees with nothing but time on their hands.

The pension program, which had been in place for almost a decade, led to delayed recall, especially among women, supporting “the mental retirement hypothesis that decreased mental activity results in worsening cognitive skills,” the investigators said in a written statement.

There also was a drop in social engagement, with lower rates of volunteering and social interaction than people who didn’t receive the pension. Some behaviors, like regular alcohol consumption, did improve over the previous year, as did total health in general, but “the adverse effects of early retirement on mental and social engagement significantly outweigh the program’s protective effect on various health behaviors,” Plamen Nikolov, PhD, said about his research.

So if you’re looking to retire early, don’t skimp on the crosswords and the bingo nights. Stay busy in a good way. Your brain will thank you.
 

Indiana Jones and the First Smallpox Ancestor

Smallpox was, not that long ago, one of the most devastating diseases known to humanity, killing 300 million people in the 20th century alone. Eradicating it has to be one of medicine’s crowning achievements. Now it can only be found in museums, which is where it belongs.

J. Nakano, USCDCP/Pixnio

Here’s the thing with smallpox though: For all it did to us, we know frustratingly little about where it came from. Until very recently, the best available genetic evidence placed its emergence in the 17th century, which clashes with historical data. You know what that means, right? It’s time to dig out the fedora and whip, cue the music, and dig into a recently published study spanning continents in search of the mythical smallpox origin story.

We pick up in 2020, when genetic evidence definitively showed smallpox in a Viking burial site, moving the disease’s emergence a thousand years earlier. Which is all well and good, but there’s solid visual evidence that Egyptian pharaohs were dying of smallpox, as their bodies show the signature scarring. Historians were pretty sure smallpox went back about 4,000 years, but there was no genetic material to prove it.

Since there aren’t any 4,000-year-old smallpox germs laying around, the researchers chose to attack the problem another way – by burning down a Venetian catacomb, er, conducting a analysis of historical smallpox genetics to find the virus’s origin. By analyzing the genomes of various strains at different periods of time, they were able to determine that the variola virus had a definitive common ancestor. Some of the genetic components in the Viking-age sample, for example, persisted until the 18th century.

Armed with this information, the scientists determined that the first smallpox ancestor emerged about 3,800 years ago. That’s very close to the historians’ estimate for the disease’s emergence. Proof at last of smallpox’s truly ancient origin. One might even say the researchers chose wisely.
 

The only hall of fame that really matters

LOTME loves the holiday season – the food, the gifts, the radio stations that play nothing but Christmas music – but for us the most wonderful time of the year comes just a bit later. No, it’s not our annual Golden Globes slap bet. Nope, not even the “excitement” of the College Football Playoff National Championship. It’s time for the National Inventors Hall of Fame to announce its latest inductees, and we could hardly sleep last night after putting cookies out for Thomas Edison. Fasten your seatbelts!

National Inventors Hall of Fame

• Robert G. Bryant is a NASA chemist who developed Langley Research Center-Soluble Imide (yes, that’s the actual name) a polymer used as an insulation material for leads in implantable cardiac resynchronization therapy devices.
• Rory Cooper is a biomedical engineer who was paralyzed in a bicycle accident. His work has improved manual and electric wheelchairs and advanced the health, mobility, and social inclusion of people with disabilities and older adults. He is also the first NIHF inductee named Rory.
• Katalin Karikó, a biochemist, and Drew Weissman, an immunologist, “discovered how to enable messenger ribonucleic acid (mRNA) to enter cells without triggering the body’s immune system,” NIHF said, and that laid the foundation for the mRNA COVID-19 vaccines developed by Pfizer-BioNTech and Moderna. That, of course, led to the antivax movement, which has provided so much LOTME fodder over the years.
• Angela Hartley Brodie was a biochemist who discovered and developed a class of drugs called aromatase inhibitors, which can stop the production of hormones that fuel cancer cell growth and are used to treat breast cancer in 500,000 women worldwide each year.

We can’t mention all of the inductees for 2023 (our editor made that very clear), but we would like to offer a special shout-out to brothers Cyril (the first Cyril in the NIHF, by the way) and Louis Keller, who invented the world’s first compact loader, which eventually became the Bobcat skid-steer loader. Not really medical, you’re probably thinking, but we’re sure that someone, somewhere, at some time, used one to build a hospital, landscape a hospital, or clean up after the demolition of a hospital.

The ‘scheme’ in the name should have been a clue

Retirement. The shiny reward to a lifetime’s worth of working and saving. We’re all literally working to get there, some of us more to get there early, but current research reveals that early retirement isn’t the relaxing finish line we dream about, cognitively speaking.

FatCamera/Getty Images

Researchers at Binghamton (N.Y.) University set out to examine just how retirement plans affect cognitive performance. They started off with China’s New Rural Pension Scheme (scheme probably has a less negative connotation in Chinese), a plan that financially aids the growing rural retirement-age population in the country. Then they looked at data from the Chinese Health and Retirement Longitudinal Survey, which tests cognition with a focus on episodic memory and parts of intact mental status.

What they found was the opposite of what you would expect out of retirees with nothing but time on their hands.

The pension program, which had been in place for almost a decade, led to delayed recall, especially among women, supporting “the mental retirement hypothesis that decreased mental activity results in worsening cognitive skills,” the investigators said in a written statement.

There also was a drop in social engagement, with lower rates of volunteering and social interaction than people who didn’t receive the pension. Some behaviors, like regular alcohol consumption, did improve over the previous year, as did total health in general, but “the adverse effects of early retirement on mental and social engagement significantly outweigh the program’s protective effect on various health behaviors,” Plamen Nikolov, PhD, said about his research.

So if you’re looking to retire early, don’t skimp on the crosswords and the bingo nights. Stay busy in a good way. Your brain will thank you.
 

Indiana Jones and the First Smallpox Ancestor

Smallpox was, not that long ago, one of the most devastating diseases known to humanity, killing 300 million people in the 20th century alone. Eradicating it has to be one of medicine’s crowning achievements. Now it can only be found in museums, which is where it belongs.

J. Nakano, USCDCP/Pixnio

Here’s the thing with smallpox though: For all it did to us, we know frustratingly little about where it came from. Until very recently, the best available genetic evidence placed its emergence in the 17th century, which clashes with historical data. You know what that means, right? It’s time to dig out the fedora and whip, cue the music, and dig into a recently published study spanning continents in search of the mythical smallpox origin story.

We pick up in 2020, when genetic evidence definitively showed smallpox in a Viking burial site, moving the disease’s emergence a thousand years earlier. Which is all well and good, but there’s solid visual evidence that Egyptian pharaohs were dying of smallpox, as their bodies show the signature scarring. Historians were pretty sure smallpox went back about 4,000 years, but there was no genetic material to prove it.

Since there aren’t any 4,000-year-old smallpox germs laying around, the researchers chose to attack the problem another way – by burning down a Venetian catacomb, er, conducting a analysis of historical smallpox genetics to find the virus’s origin. By analyzing the genomes of various strains at different periods of time, they were able to determine that the variola virus had a definitive common ancestor. Some of the genetic components in the Viking-age sample, for example, persisted until the 18th century.

Armed with this information, the scientists determined that the first smallpox ancestor emerged about 3,800 years ago. That’s very close to the historians’ estimate for the disease’s emergence. Proof at last of smallpox’s truly ancient origin. One might even say the researchers chose wisely.
 

The only hall of fame that really matters

LOTME loves the holiday season – the food, the gifts, the radio stations that play nothing but Christmas music – but for us the most wonderful time of the year comes just a bit later. No, it’s not our annual Golden Globes slap bet. Nope, not even the “excitement” of the College Football Playoff National Championship. It’s time for the National Inventors Hall of Fame to announce its latest inductees, and we could hardly sleep last night after putting cookies out for Thomas Edison. Fasten your seatbelts!

National Inventors Hall of Fame

• Robert G. Bryant is a NASA chemist who developed Langley Research Center-Soluble Imide (yes, that’s the actual name) a polymer used as an insulation material for leads in implantable cardiac resynchronization therapy devices.
• Rory Cooper is a biomedical engineer who was paralyzed in a bicycle accident. His work has improved manual and electric wheelchairs and advanced the health, mobility, and social inclusion of people with disabilities and older adults. He is also the first NIHF inductee named Rory.
• Katalin Karikó, a biochemist, and Drew Weissman, an immunologist, “discovered how to enable messenger ribonucleic acid (mRNA) to enter cells without triggering the body’s immune system,” NIHF said, and that laid the foundation for the mRNA COVID-19 vaccines developed by Pfizer-BioNTech and Moderna. That, of course, led to the antivax movement, which has provided so much LOTME fodder over the years.
• Angela Hartley Brodie was a biochemist who discovered and developed a class of drugs called aromatase inhibitors, which can stop the production of hormones that fuel cancer cell growth and are used to treat breast cancer in 500,000 women worldwide each year.

We can’t mention all of the inductees for 2023 (our editor made that very clear), but we would like to offer a special shout-out to brothers Cyril (the first Cyril in the NIHF, by the way) and Louis Keller, who invented the world’s first compact loader, which eventually became the Bobcat skid-steer loader. Not really medical, you’re probably thinking, but we’re sure that someone, somewhere, at some time, used one to build a hospital, landscape a hospital, or clean up after the demolition of a hospital.

The ‘scheme’ in the name should have been a clue

Retirement. The shiny reward to a lifetime’s worth of working and saving. We’re all literally working to get there, some of us more to get there early, but current research reveals that early retirement isn’t the relaxing finish line we dream about, cognitively speaking.

FatCamera/Getty Images

Researchers at Binghamton (N.Y.) University set out to examine just how retirement plans affect cognitive performance. They started off with China’s New Rural Pension Scheme (scheme probably has a less negative connotation in Chinese), a plan that financially aids the growing rural retirement-age population in the country. Then they looked at data from the Chinese Health and Retirement Longitudinal Survey, which tests cognition with a focus on episodic memory and parts of intact mental status.

What they found was the opposite of what you would expect out of retirees with nothing but time on their hands.

The pension program, which had been in place for almost a decade, led to delayed recall, especially among women, supporting “the mental retirement hypothesis that decreased mental activity results in worsening cognitive skills,” the investigators said in a written statement.

There also was a drop in social engagement, with lower rates of volunteering and social interaction than people who didn’t receive the pension. Some behaviors, like regular alcohol consumption, did improve over the previous year, as did total health in general, but “the adverse effects of early retirement on mental and social engagement significantly outweigh the program’s protective effect on various health behaviors,” Plamen Nikolov, PhD, said about his research.

So if you’re looking to retire early, don’t skimp on the crosswords and the bingo nights. Stay busy in a good way. Your brain will thank you.
 

Indiana Jones and the First Smallpox Ancestor

Smallpox was, not that long ago, one of the most devastating diseases known to humanity, killing 300 million people in the 20th century alone. Eradicating it has to be one of medicine’s crowning achievements. Now it can only be found in museums, which is where it belongs.

J. Nakano, USCDCP/Pixnio

Here’s the thing with smallpox though: For all it did to us, we know frustratingly little about where it came from. Until very recently, the best available genetic evidence placed its emergence in the 17th century, which clashes with historical data. You know what that means, right? It’s time to dig out the fedora and whip, cue the music, and dig into a recently published study spanning continents in search of the mythical smallpox origin story.

We pick up in 2020, when genetic evidence definitively showed smallpox in a Viking burial site, moving the disease’s emergence a thousand years earlier. Which is all well and good, but there’s solid visual evidence that Egyptian pharaohs were dying of smallpox, as their bodies show the signature scarring. Historians were pretty sure smallpox went back about 4,000 years, but there was no genetic material to prove it.

Since there aren’t any 4,000-year-old smallpox germs laying around, the researchers chose to attack the problem another way – by burning down a Venetian catacomb, er, conducting a analysis of historical smallpox genetics to find the virus’s origin. By analyzing the genomes of various strains at different periods of time, they were able to determine that the variola virus had a definitive common ancestor. Some of the genetic components in the Viking-age sample, for example, persisted until the 18th century.

Armed with this information, the scientists determined that the first smallpox ancestor emerged about 3,800 years ago. That’s very close to the historians’ estimate for the disease’s emergence. Proof at last of smallpox’s truly ancient origin. One might even say the researchers chose wisely.
 

The only hall of fame that really matters

LOTME loves the holiday season – the food, the gifts, the radio stations that play nothing but Christmas music – but for us the most wonderful time of the year comes just a bit later. No, it’s not our annual Golden Globes slap bet. Nope, not even the “excitement” of the College Football Playoff National Championship. It’s time for the National Inventors Hall of Fame to announce its latest inductees, and we could hardly sleep last night after putting cookies out for Thomas Edison. Fasten your seatbelts!

National Inventors Hall of Fame

• Robert G. Bryant is a NASA chemist who developed Langley Research Center-Soluble Imide (yes, that’s the actual name) a polymer used as an insulation material for leads in implantable cardiac resynchronization therapy devices.
• Rory Cooper is a biomedical engineer who was paralyzed in a bicycle accident. His work has improved manual and electric wheelchairs and advanced the health, mobility, and social inclusion of people with disabilities and older adults. He is also the first NIHF inductee named Rory.
• Katalin Karikó, a biochemist, and Drew Weissman, an immunologist, “discovered how to enable messenger ribonucleic acid (mRNA) to enter cells without triggering the body’s immune system,” NIHF said, and that laid the foundation for the mRNA COVID-19 vaccines developed by Pfizer-BioNTech and Moderna. That, of course, led to the antivax movement, which has provided so much LOTME fodder over the years.
• Angela Hartley Brodie was a biochemist who discovered and developed a class of drugs called aromatase inhibitors, which can stop the production of hormones that fuel cancer cell growth and are used to treat breast cancer in 500,000 women worldwide each year.

We can’t mention all of the inductees for 2023 (our editor made that very clear), but we would like to offer a special shout-out to brothers Cyril (the first Cyril in the NIHF, by the way) and Louis Keller, who invented the world’s first compact loader, which eventually became the Bobcat skid-steer loader. Not really medical, you’re probably thinking, but we’re sure that someone, somewhere, at some time, used one to build a hospital, landscape a hospital, or clean up after the demolition of a hospital.

The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

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

The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

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

The 2022 guideline update released by the KDIGO organization for managing people with diabetes and chronic kidney disease (CKD) highlighted the safety and expanded, evidence-based role for agents from three drug classes: the SGLT2 inhibitors, the GLP-1 receptor agonists, and the nonsteroidal mineralocorticoid receptor antagonists.

But this key take-away from the guideline also underscored the challenges for ensuring fair and affordable access among US patients to these practice-changing medications.

The impact of widespread adoption of these three drug classes into routine US management of people with diabetes and CKD “will be determined by how effective the health care system and its patients and clinicians are at overcoming individual and structural barriers,” write Milda Saunders, MD, and Neda Laiteerapong, MD, in an editorial that accompanied the publication of a synopsis of the 2022 guideline update in Annals of Internal Medicine.

The synopsis is an 11-page distillation of the full 128-page guideline released by the Kidney Disease: Improving Global Outcomes (KDIGO) organization in 2022.

The recommendations in the 2022 guideline update “are exciting for their potential to change the natural history of CKD and diabetes, but their effect could be highly limited by barriers at multiple levels,” write Dr. Saunders and Dr. Laiteerapong, two internal medicine physicians at the University of Chicago.

“Without equitable implementation of the KDIGO 2022 guidelines there is a potential that clinical practice variation will increase and widen health inequities for minoritized people with CKD and diabetes,” they warn.
 

Generics to the rescue

One potentially effective, and likely imminent, way to level the prescribing field for patients with CKD and diabetes is for agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor, glucagonlike peptide-1 (GLP-1) receptor agonist, and nonsteroidal mineralocorticoid receptor antagonist classes to become available in generic formulations.

That should lower prices and thereby boost wider access and will likely occur fairly soon for at least two of the three drug classes, Dr. Laiteerapong predicts.

Some GLP-1 receptor agonists have already escaped patent exclusivity or will do so in 2023, she notes, including the anticipated ability of one drugmaker to start U.S. marketing of generic liraglutide by the end of 2023.

However, whether that manufacturer, Teva, proceeds with generic liraglutide “is a big question,” Dr. Laiteerapong said in an interview. She cited Teva’s history of failing to introduce a generic formulation of exenatide onto the U.S. market even though it has had a green light to do so since 2017.

The only nonsteroidal mineralocorticoid receptor antagonist now on the market is finerenone (Kerendia), which will not go off patent for several more years, but for some branded SGLT2 inhibitors, U.S. patents will expire in 2025. In addition, remogliflozin is an SGLT2 inhibitor that “may have already lost patent exclusivity,” noted Dr. Laiteerapong, although it has also never received U.S. marketing approval.

Dr. Laiteerapong expressed optimism that the overall trajectory of access is on the rise. “Many people have type 2 diabetes, and these drugs are in demand,” she noted. She also pointed to progress recently made on insulin affordability. “Things will get better as long as people advocate and argue for equity,” she maintained.
 

Incentivize formulary listings

Dr. Laiteerapong cited other approaches that could boost access to these medications, such as “creating incentives for pharmaceutical companies to ensure that [these drugs] are on formularies” of large, government-affiliated U.S. health insurance programs, such as Medicare Advantage plans, Medicare Part D, state Medicaid plans, and coverage through U.S. Veterans Affairs and the Tricare health insurance plans available to active members of the US military.

The editorial she coauthored with Dr. Saunders also calls for future collaborations among various medical societies to create “a more unified and streamlined set of recommendations” that benefits patients with diabetes, CKD, and multiple other chronic conditions.

“Over the last decade, we have seen more societies willing to present cooperative guidelines, as well as a surge in research on patients who live with multiple chronic conditions. There is momentum that will allow these different societies to work together,” Dr. Laiteerapong said.

Dr. Laiteerapong and Dr. Saunders have disclosed no relevant financial relationships.

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

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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

Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.

During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.

The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.

PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).

The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
 

Prior observational reports

For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)

And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.

However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.

U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
 

Long-term PPI use threatens harm

“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”

The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.

The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine₂ receptor antagonists, a drug class with indications similar to those for PPIs.

The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.

The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.

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

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

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

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

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

Patients with acute decompensated heart failure who were frail at baseline improved more with targeted, early physical rehabilitation than those who were prefrail, a new analysis of the REHAB-HF study suggests.

“The robust response to the intervention by frail patients exceeded our expectations,” Gordon R. Reeves, MD, PT, of Novant Health Heart and Vascular Institute, Charlotte, N.C., told this news organization. “The effect size from improvement in physical function among frail patients was very large, with at least four times the minimal meaningful improvement, based on the Short Physical Performance Battery (SPPB).”

Furthermore, the interaction between baseline frailty status and treatment in REHAB-HF was such that a 2.6-fold larger improvement in SPPB was seen among frail versus prefrail patients.

However, Dr. Reeves noted, “We need to further evaluate safety and efficacy as it relates to adverse clinical events. Specifically, we observed a numerically higher number of deaths with the REHAB-HF intervention, which warrants further investigation before the intervention is implemented in clinical practice.”

The study was published online  in JAMA Cardiology.
 

Interpret with caution

Dr. Reeves and colleagues conducted a prespecified secondary analysis of the previously published Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial, a multicenter, randomized controlled trial that showed that a 3-month early, transitional, tailored, multidomain physical rehabilitation intervention improved physical function and quality of life (QoL), compared with usual care. The secondary analysis aimed to evaluate whether baseline frailty altered the benefits of the intervention or was associated with risk of adverse outcomes.

According to Dr. Reeves, REHAB-HF differs from more traditional cardiac rehab programs in several ways.

• The intervention targets patients with acute HF, including HF with preserved ejection fraction (HFpEF). Medicare policy limits standard cardiac rehabilitation in HF to long-term patients with HF with reduced ejection fraction (HFrEF) only who have been stabilized for 6 weeks or longer after a recent hospitalization.
• It addresses multiple physical function domains, including balance, mobility, functional strength, and endurance. Standard cardiac rehab is primarily focused on endurance training, which can result in injuries and falls if deficits in balance, mobility, and strength are not addressed first.
• It is delivered one to one rather than in a group setting and primarily by physical therapists who are experts in the rehabilitation of medically complex patients.
• It is transitional, beginning in the hospital, then moving to the outpatient setting, then to home and includes a home assessment.

For the analysis, the Fried phenotype model was used to assess baseline frailty across five domains: unintentional weight loss during the past year; self-reported exhaustion; grip strength; slowness, as assessed by gait speed; and low physical activity, as assessed by the Short Form-12 Physical Composite Score.

At the baseline visit, patients were categorized as frail if they met three or more of these criteria. They were categorized as prefrail if they met one or two criteria and as nonfrail if they met none of the criteria. Because of the small number of nonfrail participants, the analysis included only frail and prefrail participants.

The analysis included 337 participants (mean age, 72; 54%, women; 50%, Black). At baseline, 57% were frail, and 43% were prefrail.

A significant interaction was seen between baseline frailty and the intervention for the primary trial endpoint of overall SPPB score, with a 2.6-fold larger improvement in SPPB among frail (2.1) versus prefrail (0.8) patients.

Trends favored a larger intervention effect size, with significant improvement among frail versus prefrail participants for 6-minute walk distance, QoL, and the geriatric depression score.

“However, we must interpret these findings with caution,” the authors write. “The REHAB-HF trial was not adequately powered to determine the effect of the intervention on clinical events.” This plus the number of deaths “underscore the need for additional research, including prospective clinical trials, investigating the effect of physical function interventions on clinical events among frail patients with HF.”

To address this need, the researchers recently launched a larger clinical trial, called REHAB-HFpEF, which is powered to assess the impact of the intervention on clinical events, according to Dr. Reeves. “As the name implies,” he said, “this trial is focused on older patients recently hospitalized with HFpEF, who, [compared with HFrEF] also showed a more robust response to the intervention, with worse physical function and very high prevalence of frailty near the time of hospital discharge.”
 

‘Never too old or sick to benefit’

Jonathan H. Whiteson, MD, vice chair of clinical operations and medical director of cardiac and pulmonary rehabilitation at NYU Langone Health’s Rusk Rehabilitation, said, “We have seen in clinical practice and in other (non–heart failure) clinical areas that frail older patients do improve proportionally more than younger and less frail patients with rehabilitation programs. Encouragingly, this very much supports the practice that patients are never too old or too sick to benefit from an individualized multidisciplinary rehabilitation program.”

However, he noted, “patients had to be independent with basic activities of daily living to be included in the study,” so many frail, elderly patients with heart failure who are not independent were not included in the study. It also wasn’t clear whether patients who received postacute care at a rehab facility before going home were included in the trial.

Furthermore, he said, outcomes over 1 to 5 years are needed to understand the long-term impact of the intervention.

On the other hand, he added, the fact that about half of participants were Black and were women is a “tremendous strength.”

“Repeating this study in population groups at high risk for frailty with different diagnoses, such as chronic lung diseases, interstitial lung diseases, chronic kidney disease, and rheumatologic disorders will further support the value of rehabilitation in improving patient health, function, quality of life, and reducing rehospitalizations and health care costs,” Dr. Whiteson concluded.

The study was supported by grants from the National Key R&D program. The authors have disclosed no relevant financial relationships.

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

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

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

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

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

Antihypertensive medications that stimulate rather than inhibit type 2 and 4 angiotensin II receptors can lower the rate of dementia among new users of these medications, new research suggests.

Results from a cohort study of more than 57,000 older Medicare beneficiaries showed that the initiation of antihypertensives that stimulate the receptors was linked to a 16% lower risk for incident Alzheimer’s disease and related dementia (ADRD) and an 18% lower risk for vascular dementia compared with those that inhibit the receptors.

“Achieving appropriate blood pressure control is essential for maximizing brain health, and this promising research suggests certain antihypertensives could yield brain benefit compared to others,” lead study author Zachary A. Marcum, PharmD, PhD, associate professor, University of Washington School of Pharmacy, Seattle, told this news organization.

The findings were published online in JAMA Network Open.
 

Medicare beneficiaries

Previous observational studies showed that antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, in comparison with those that don’t, were associated with lower rates of dementia. However, those studies included individuals with prevalent hypertension and were relatively small.

The new retrospective cohort study included a random sample of 57,773 Medicare beneficiaries aged at least 65 years with new-onset hypertension. The mean age of participants was 73.8 years, 62.9% were women, and 86.9% were White.

Over the course of the study, some participants filled at least one prescription for a stimulating angiotensin II receptor type 2 and 4, such as angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics.

Others participants filled a prescription for an inhibiting type 2 and 4 angiotensin II receptors, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and nondihydropyridine calcium channel blockers.

“All these medications lower blood pressure, but they do it in different ways,” said Dr. Marcum.

The researchers were interested in the varying activity of these drugs at the type 2 and 4 angiotensin II receptors.

For each 30-day interval, they categorized beneficiaries into four groups: a stimulating medication group (n = 4,879) consisting of individuals mostly taking stimulating antihypertensives; an inhibiting medication group (n = 10,303) that mostly included individuals prescribed this type of antihypertensive; a mixed group (n = 2,179) that included a combination of the first two classifications; and a nonuser group (n = 40,413) of individuals who were not using either type of drug.

The primary outcome was time to first occurrence of ADRD. The secondary outcome was time to first occurrence of vascular dementia.

Researchers controlled for cardiovascular risk factors and sociodemographic characteristics, such as age, sex, race/ethnicity, and receipt of low-income subsidy.
 

Unanswered questions

After adjustments, results showed that initiation of an antihypertensive medication regimen that exclusively stimulates, rather than inhibits, type 2 and 4 angiotensin II receptors was associated with a 16% lower risk for incident ADRD over a follow-up of just under 7 years (hazard ratio, 0.84; 95% confidence interval, 0.79-0.90; P < .001).

The mixed regimen was also associated with statistically significant (P = .001) reduced odds of ADRD compared with the inhibiting medications.

As for vascular dementia, use of stimulating vs. inhibiting medications was associated with an 18% lower risk (HR, 0.82; 95% CI, 0.69-0.96; P = .02).

Again, use of the mixed regimen was associated with reduced risk of vascular dementia compared with the inhibiting medications (P = .03).

A variety of potential mechanisms might explain the superiority of stimulating agents when it comes to dementia risk, said Dr. Marcum. These could include, for example, increased blood flow to the brain and reduced amyloid.

“But more mechanistic work is needed as well as evaluation of dose responses, because that’s not something we looked at in this study,” Dr. Marcum said. “There are still a lot of unanswered questions.”
 

Stimulators instead of inhibitors?

The results of the current analysis come on the heels of some previous work showing the benefits of lowering blood pressure. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that targeting a systolic blood pressure below 120 mm Hg significantly reduces risk for heart disease, stroke, and death from these diseases.

But in contrast to previous research, the current study included only beneficiaries with incident hypertension and new use of antihypertensive medications, and it adjusted for time-varying confounding.

Prescribing stimulating instead of inhibiting treatments could make a difference at the population level, Dr. Marcum noted.

“If we could shift the prescribing a little bit from inhibiting to stimulating, that could possibly reduce dementia risk,” he said.

However, “we’re not suggesting [that all patients] have their regimen switched,” he added.

That’s because inhibiting medications still have an important place in the antihypertensive treatment armamentarium, Dr. Marcum noted. As an example, beta-blockers are used post heart attack.

As well, factors such as cost and side effects should be taken into consideration when prescribing an antihypertensive drug.

The new results could be used to set up a comparison in a future randomized controlled trial that would provide the strongest evidence for estimating causal effects of treatments, said Dr. Marcum.
 

‘More convincing’

Carlos G. Santos-Gallego, MD, Icahn School of Medicine at Mount Sinai, New York, said the study is “more convincing” than previous related research, as it has a larger sample size and a longer follow-up.

“And the exquisite statistical analysis gives more robustness, more solidity, to the hypothesis that drugs that stimulate type 2 and 4 angiotensin II receptors might be protective for dementia,” said Dr. Santos-Gallego, who was not involved with the research.

However, he noted that the retrospective study had some limitations, including the underdiagnosis of dementia. “The diagnosis of dementia is, honestly, very poorly done in the clinical setting,” he said.

As well, the study could be subject to “confounding by indication,” Dr. Santos-Gallego said. “There could be a third variable, another confounding factor, that’s responsible both for the dementia and for the prescription of these drugs,” he added.

For example, he noted that comorbidities such as atrial fibrillation, myocardial infarction, and heart failure might increase the risk of dementia.

He agreed with the investigators that a randomized clinical trial would address these limitations. “All comorbidities would be equally shared” in the randomized groups, and all participants would be given “a specific test for dementia at the same time,” Dr. Santos-Gallego said.

Still, he noted that the new results are in keeping with hypertension guidelines that recommend stimulating drugs.

“This trial definitely shows that the current hypertension guidelines are good treatment for our patients, not only to control blood pressure and not only to prevent infarction to prevent stroke but also to prevent dementia,” said Dr. Santos-Gallego.

Also commenting for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said the new data provide “clarity” on why previous research had differing results on the effect of antihypertensives on cognition.

Among the caveats of this new analysis is that “it’s unclear if the demographics in this study are fully representative of Medicare beneficiaries,” said Dr. Snyder.

She, too, said a clinical trial is important “to understand if there is a preventative and/or treatment potential in the medications that stimulate type 2 and 4 angiotensin II receptors.”

The study received funding from the National Institute on Aging. Dr. Marcum and Dr. Santos-Gallego have reported no relevant financial relationships.

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

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

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

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

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

You discuss and decide on the best course of treatment for your patients, write prescriptions, and recommend lifestyle modifications to enhance treatment outcomes and overall wellness. But once they leave your office, following through is up to the patient. What happens when they don’t listen?

The term “nonadherent” has gradually replaced “noncompliant” in the physician lexicon as a nod to the evolving doctor-patient relationship. Noncompliance implies that a patient isn’t following their doctor’s orders. Adherence, on the other hand, is a measure of how closely your patient’s behavior matches the recommendations you’ve made. It’s a subtle difference but an important distinction in approaching care.

“Noncompliance is inherently negative feedback to the patient, whereas there’s a reason for nonadherence, and it’s usually external,” said Sharon Rabinovitz, MD, president of the Georgia Academy of Family Physicians.
 

Why won’t patients listen?

The reasons behind a patient’s nonadherence are multifaceted, but they are often driven by social determinants of health, such as transportation, poor health literacy, finances, and lack of access to pharmacies.

Other times, patients don’t want to take medicine, don’t prioritize their health, or they find the dietary and lifestyle modifications doctors suggest too hard to make or they struggle at losing weight, eating more healthfully, or cutting back on alcohol, for instance.

“When you come down to it, the big hindrance of it all is cost and the ability for the patient to be able to afford some of the things that we think they should be able to do,” said Teresa Lovins, MD, a physician in private practice Columbus, Ind., and a member of the board of directors of the American Academy of Family Physicians.

Another common deterrent to treatment is undesired side effects that a patient may not want to mention.

“For example, a lot of patients who are taking antidepressants have sexual dysfunction associated with those medications,” said Dr. Rabinovitz. “If you don’t ask the right questions, you’re not going to be able to fully assess the experience the patient is having and a reason why they might not take it [the medication].”

Much nonadherence is intentional and is based on experience, belief systems, and knowledge. For example, the American Medical Association finds that patients may not understand why they need a certain treatment (and therefore dismiss it), or they may be overloaded with multiple medications, fear dependency on a drug, have a mistrust of pharmaceutical companies or the medical system as a whole, or have symptoms of depression that make taking healthy actions more difficult. In addition, patients may be unable to afford their medication, or their lack of symptoms may lead them to believe they don’t really need the prescription, as occurs with disorders such as hypertension or high cholesterol.

“In my training, we did something called Balint training, where we would get together as a group with attendings and discuss cases that were difficult from a biopsychosocial perspective and consider all the factors in the patient perspective, including family dynamics, social systems, and economic realities,” said Russell Blackwelder, MD, director of geriatric education and associate professor of family medicine at the Medical University of South Carolina, Charleston.

“That training was, for me, very helpful for opening up and being more empathetic and really examining the patient’s point of view and everything that impacts them.”

Dr. Lovins agreed that it’s crucial to establish a good rapport and build mutual trust.

“If you don’t know the patient, you have a harder time asking the right questions to get to the meat of why they’re not taking their medicine or what they’re not doing to help their health,” she said. “It takes a little bit of trust on both parts to get to that question that really gets to the heart of why they’re not doing what you’re asking them to do.”
 

How to encourage adherence

Although there may not be a one-size-fits-all approach for achieving general adherence or adherence to a medication regimen, some methods may increase success.

Kenneth Zweig, MD, an internist at Northern Virginia Family Practice Associates, Alexandria, said that convincing patients to make one small change that they can sustain can get the ball rolling.

“I had one patient who was very overweight and had high blood pressure, high cholesterol, back pain, insomnia, and depression, who was also drinking three to four beers a night,” Dr. Zweig said. “After a long discussion, I challenged him to stop all alcohol for 1 week. At the end of the week, he noticed that he slept better, lost some weight, had lower blood pressure, and had more energy. Once he saw the benefits of this one change, he was motivated to improve other aspects of his health as well. He improved his diet, started exercising, and lost over 50 pounds. He has persisted with these lifestyle changes ever since.”

A team-based approach may also increase treatment understanding and adherence. In one older study, patients who were assigned to team-based care, including care by pharmacists, were significantly more adherent to medication regimens. Patients were more comfortable asking questions and raising concerns when they felt their treatment plan was a collaboration between several providers and themselves.

Dr. Lovins said to always approach the patient with a positive. “Say, what can we do together to make this work? What are your questions about this medication? And try and focus on the positive things that you can change instead of leaving the patient with a negative feeling or that you’re angry with them or that you’re unhappy with their choices. Patients respond better when they are treated as part of the team.”

Fear of judgment can also be a barrier to honesty between patients and their doctors. Shame creates a reluctance to admit nonadherence. Dr. Lovins said in an interview that it’s the physician’s responsibility to create a blame-free space for patients to speak openly about their struggles with treatment and reasons for nonadherence.
 

When should you redirect care?

Ultimately, the goal is good care and treatment of disease. However, if you and your patient are at an impasse and progress is stalling or failing, it may be appropriate to encourage the patient to seek care elsewhere.

“Just like any relationship, some physician-patient relationships are just not a good fit,” said Dr. Blackwelder. And this may be the reason why the patient is nonadherent — something between the two of you doesn’t click.

While there are ethical considerations for this decision, most medical boards have guidelines on how to go about it, Dr. Blackwelder said in an interview. “In the state of South Carolina, we have to be available to provide urgent coverage for at least 30 days and notify the patient in writing that they need to find somebody else and to help them find somebody else if we can.”

Just as with care, a clear conversation is the best practice if you’re proposing a potential shift away from a physician-patient relationship. You might say: We’re not making the kind of progress I’d like to see, and I’m wondering if you think working with another doctor may help you.

“The most important thing is being very honest and transparent with the patient that you’re concerned you’re not making the appropriate strides forward,” said Dr. Rabinovitz. Then you can ask, ‘Am I the right doctor to help you reach your goals? And if not, how can I help you get to where you need to be?’ ”

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

Patients with thrombotic antiphospholipid syndrome are better treated with a vitamin K antagonist, such as warfarin, rather than a direct oral anticoagulant (DOAC), a new systematic review and meta-analysis suggests.

“Our study is showing that in randomized controlled trials in patients with thrombotic antiphospholipid syndrome, the risk of arterial thrombotic events, particularly stroke, is significantly increased with DOACs vs. vitamin K antagonists,” senior author, Behnood Bikdeli, MD, Brigham and Women’s Hospital, Boston, told this news organization. “These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome.”

The study was published online in the Journal of the American College of Cardiology.
 

Autoimmune disorder

Thrombotic antiphospholipid syndrome is a systemic autoimmune disorder characterized by recurrent arterial and/or venous thrombotic events.

Dr. Bikdeli estimates that antiphospholipid syndrome is the cause of 50,000-100,000 strokes, 100,000 cases of myocardial infarction, and 30,000 cases of deep vein thrombosis every year.

“It is a serious condition, and these are a high-risk and complex group of patients,” he said.

The standard treatment has been anticoagulation with a vitamin K antagonist such as warfarin. “But this is a cumbersome treatment, with many drug interactions and the need for INR [International Normalized Ratio] monitoring, which can be difficult to manage in patients with antiphospholipid syndrome as there can sometimes be falsely abnormal numbers,” Dr. Bikdeli noted. “Because of these challenges, it looked very promising to explore the use of DOACs in this population.”

Four main randomized trials have been conducted to investigate the use of DOACs in antiphospholipid syndrome – three with rivaroxaban and one with apixaban. “These trials were all quite small and, while they did not show definite results, some of them suggested nonsignificant findings of slightly worse outcomes for DOACs vs. vitamin K antagonists. But there is a lot of uncertainty, and it is difficult to look at subgroups in such small trials,” Dr. Bikdeli said. “There are many questions remaining about whether we should use DOACs in patients with antiphospholipid syndrome and, if so, which particular subgroups.”

The authors therefore performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists in patients with antiphospholipid syndrome. They also contacted the principal investigators of the trials to obtain additional unpublished aggregate level data on specific subgroups.

Four open-label randomized controlled trials involving 472 patients were included in the meta-analysis.

Overall, the use of DOACs, compared with vitamin K antagonists, was associated with increased odds of subsequent arterial thrombotic events (odds ratio, 5.43; P < .001), especially stroke.

The odds of subsequent venous thrombotic events or major bleeding were not significantly different between the two groups. Most findings were consistent within subgroups.

“Our results show that use of DOACs vs. vitamin K antagonists is associated with increased risk of arterial thrombotic events – a risk that is primarily driven by a significant increase in the risk of stroke,” Dr. Bikdeli commented.

When looking at subgroups of interest, it was previously thought that DOACs may not be so effective in the so-called “triple-positive” antiphospholipid patients. These patients have three different types of antibodies and have the highest risk of thrombosis, Dr. Bikdeli noted.

“But one of the interesting findings of our study is that the results are actually consistent in women vs. men and in people who have triple-positive antibodies and those who had double- or single-positive antibodies,” he said. “Our analyses did not show effect modification by antibody subgroups. They suggest similar trends towards worse outcomes in all subgroups.”   

“From these results, I would be similarly concerned to use DOACs even if someone has double-positive or single-positive antiphospholipid antibodies,” he added.

Dr. Bikdeli said he would still recommend shared decision-making with patients. “If I have a patient who has thrombotic antiphospholipid syndrome, I would share my reservation about DOACs, but there are multiple factors that come into decision-making. If someone has difficulty with checking INRs, we may make an informed choice and still use a DOAC, but patients need to know that there is likely an excess risk of subsequent arterial events with DOACs, compared with a vitamin K antagonist.”

He noted that it is still not completely clear on the situation for people with single-positive antiphospholipid syndrome or the type of antibody that is present. It is also possible that a higher dose of DOAC could be more effective, a strategy that is being investigated in a separate randomized trial currently ongoing.

“But for routine practice I would have concerns about using DOACs in antiphospholipid syndrome patients in general,” he said. “For triple positive there is more data and greater concern, but I wouldn’t give a pass for a double- or single-positive patient either.”

The reason why DOACs would be less effective than vitamin K antagonists in antiphospholipid syndrome is not known.

“That is the million-dollar question,” Dr. Bikdeli commented. “DOACs have been such helpful drugs for many patients and clinicians as well. But we have seen that they are not optimal in a series of scenarios now – patients with mechanical heart valves, patients with rheumatic [atrial fibrillaton], and now patients with thrombotic antiphospholipid syndrome.”

One hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful, compared with the more targeted DOAC therapy. “But I think we need more studies to fully understand this,” he said.

‘Important implications’

In an accompanying editorial,Mark A. Crowther, MD, McMaster University, Hamilton, Ont., and Aubrey E. Jones, PharmD, and Daniel M. Witt, PharmD, both of the University of Utah College of Pharmacy, Salt Lake City, say that: “As the quality of the evidence was rated ‘high’ for the arterial thrombosis outcome and ‘moderate’ for the venous thrombosis and bleeding outcomes, these results should lead to a revision of evidence-based guidelines to recommend against using DOACs as an option for most patients with thrombotic antiphospholipid syndrome.”

They add that this recommendation for vitamin K antagonists also applies to patients previously thought to be at lower risk from antiphospholipid syndrome – including those with only one or two positive serological tests and those with only prior venous thrombosis.

The editorialists point out that this will have important implications, particularly for the accurate diagnosis of antiphospholipid syndrome, including confirmation and documentation of positive laboratory tests at least 12 weeks after the initial positive test.

They recommend that while awaiting confirmatory testing, patients with suspected antiphospholipid syndrome should avoid DOACs, and that “strong consideration” should be given to switching essentially all antiphospholipid syndrome patients currently receiving DOACs to vitamin K antagonists.

Dr. Bikdeli is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters and is supported by the Scott Schoen and Nancy Adams IGNITE Award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital and a Career Development Award from the American Heart Association and VIVA Physicians. Dr. Crowther has received personal funding from AstraZeneca, Precision Biologics, Hemostasis Reference Laboratories, Syneos Health, Bayer, Pfizer, and CSL Behring; and holds the Leo Pharma Chair in Thromboembolism Research, which is endowed at McMaster University. Dr. Jones is supported by a career development award from the National Heart, Lung, and Blood Institute; and Dr. Witt is supported by grant funding from the Agency for Healthcare Research and Quality.

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

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today is Sandeep Jauhar, a practicing cardiologist and professor of medicine at Northwell Health, a frequent New York Times op-ed contributor, and highly regarded author of the upcoming book “My Father’s Brain: Life in the Shadow of Alzheimer’s.”

We are here today to discuss the rationale for age competency exams for practicing physicians.

Sandeep Jauhar, MD: Thanks for having me.

Dr. Glatter: Your recent op-ed piece in the New York Times caught my eye. In your piece, you refer to a 2020 survey in which almost one-third of licensed doctors in the United States were 60 years of age or older, up from a quarter in 2010. You also state that, due to a 20% prevalence of mild cognitive impairment in persons older than 65, practicing physicians above this age should probably be screened by a battery of tests to ensure that their reasoning and cognitive abilities are intact. The title of the article is “How Would You Feel About a 100-Year-Old Doctor?”

How would you envision such a process? What aspects of day-to-day functioning would the exams truly be evaluating?

Dr. Jauhar: A significant number of people over 65 have measurable cognitive impairment. By cognitive impairment, we’re not talking about dementia. The best estimates are that 1 in 10 people over age 65 have dementia, and roughly 1 in 5 have what’s called MCI, or mild cognitive impairment, which is cognitive impairment out of proportion to what you’d expect from normal aging. It’s a significant issue.

The argument that I made in the op-ed is that neurocognitive assessment is important. That’s not to say that everyone over age 65 has significant cognitive impairment or that older doctors can’t practice medicine safely and effectively. They absolutely can. The question is, do we leave neurocognitive assessment to physicians who may possibly be suffering from impairment?

In dementia, people very often have impaired self-awareness, a condition called anosognosia, which is a neurological term for not being aware of your own impairment because of your impairment.

I would argue that, instead of having voluntary neurocognitive screening, it should be mandated. The question is how to do that effectively, fairly, and transparently.

One could argue a gerontocracy in medicine today, where there are so many older physicians. What do we do about that? That really is something that I think needs to be debated.

Dr. Glatter: The question I have is, if we (that is, physicians and the health care profession) don’t take care of this, someone’s going to do it for us. We need to jump on this now while we have the opportunity. The AMA has been opposed to this, except when you have reason to suspect cognitive decline or are concerned about patient safety. A mandatory age of retirement is certainly something they’re not for, and we know this.

Your argument in your op-ed piece is very well thought out, and you lay the groundwork for testing (looking at someone’s memory, coordination, processing speed, and other executive functions). Certainly, for a psychiatrist, hearing is important, and for a dermatologist, vision is important. For a surgeon, there are other issues. Based on the specialty, we must be careful to see the important aspects of functioning. I am sure you would agree with this.

Dr. Jauhar: Obviously, the hand skills that are important for ophthalmological surgery certainly aren’t required for office-based psychological counseling, for example. We have to be smart about how we assess impairment.

You describe the spectrum of actions. On the one hand, there’s mandatory retirement at the age of 65 or 70 years. We know that commercial pilots are mandated to essentially retire at 65, and air-traffic controllers must retire in their late 50s.

We know that there’s a large amount of variability in competence. There are internists in their 80s with whom I’ve worked, and I’m absolutely wowed by their experience and judgment. There are new medical resident graduates who don’t really seem to have the requisite level of competence that would make me feel comfortable to have them as my doctor or a doctor for a member of my family.

To mandate retirement, I think the AMA is absolutely right. To not call for any kind of competency testing, to me, seems equally unwise. Because at the end of the day, you have to balance individual physician needs or wants to continue practicing with patient safety. I haven’t really come across too many physicians who say, “There’s absolutely no need for a competency testing.”

We have to meet somewhere in the middle. The middle is either voluntary cognitive competency testing or mandatory. I would argue that, because we know that as the brain changes we have cognitive impairment, but we’re not always aware that we need help, mandatory testing is the way.

One other thing that you mentioned was about having the solution imposed on us. You and I are doctors. We deal with bureaucracy. We deal with poorly thought-out solutions to issues in health care that make our lives that much more difficult. I don’t want that solution imposed on us by some outside agency. I think we need to figure this out within medicine and figure out the right way of doing it.

The AMA is on board with this. They haven’t called for mandatory testing, but they have said that if testing were to occur, these are the guidelines. The guidelines are fair and equitable, not too time-consuming, transparent, and not punitive. If someone comes out and doesn’t test well, we shouldn’t force them out of the profession. We can find ways to use their experience to help train younger doctors, for example.

Dr. Glatter: I wanted to segue to an area where there has been some challenge to the legality of these mandatory types of age restrictions and imposing the exams as well. There’s been a lawsuit as well by the EEOC [Equal Employment Opportunity Commission], on behalf of Yale. Basically, there’s been a concern that ageism is part of what’s going on. Yale now screens their providers beginning at age 70, and they have a program. UCSD [University of California, San Diego] has a program in place. Obviously, these institutions are looking at it. This is a very small part of the overall picture.

Health care systems overall, we’re talking about a fraction of them in the country are really addressing the issue of competency exams. The question is, where do we go from here? How do we get engagement or adoption and get physicians as a whole to embrace this concept?

Dr. Jauhar: The EEOC filed a lawsuit on behalf of the Yale medical staff that argued that Yale’s plan to do vision testing and neurocognitive screening – there may be a physical exam also – constitutes age discrimination because it’s reserved for doctors over the age of 70. Those are the physicians who are most likely to have cognitive impairment.

We have rules already for impaired physicians who are, for example, addicted to illicit drugs or have alcohol abuse. We already have some of those measures in place. This is focused on cognitive impairment in aging physicians because cognitive impairment is an issue that arises with aging. We have to be clear about that.

Most younger physicians will not have measurable cognitive impairment that would impair their ability to practice. To force young physicians (for example, physicians in their forties) to undergo such screening, all in the name of preventing age discrimination, doesn’t strike me as being a good use of resources. They’re more likely to be false positives, as you know from Bayesian statistics. When you have low pretest probability, you’re more likely to get false positives.

How are we going to screen hundreds of thousands of physicians? We have to make a choice about the group that really is more likely to benefit from such screening. Very few hospitals are addressing this issue and it’s going to become more important.

Dr. Glatter: Surgeons have been particularly active in pushing for age-based screening. In 2016, the American College of Surgeons started making surgeons at age 65-70 undergo voluntary health and neurocognitive assessments, and encouraged physicians to disclose any concerning findings as part of their professional obligation, which is pretty impressive in my mind.

Surgeons’ skill set is quite demanding physically and technically. That the Society of Surgical Chairs took it upon themselves to institute this is pretty telling.

Dr. Jauhar: The overall society called for screening, but then in a separate survey of surgical chairs, the idea was advanced that we should have mandatory retirement. Now, I don’t particularly agree with that.

I’ve seen it, where you have the aging surgeon who was a star in their day, and no one wants to say anything when their skills have visibly degraded, and no one wants to carry that torch and tell them that they need to retire. What happens is people whisper, and unfortunately, bad outcomes have to occur before people tend to get involved, and that’s what I’m trying to prevent.

Dr. Glatter: The question is whether older physicians have worse patient outcomes. The evidence is inconclusive, but studies have shown higher mortality rates for cardiovascular surgeons in terms of the procedures that they do. On the flip side, there are also higher mortality rates for GI surgery performed by younger surgeons. It’s a mixed bag.

Dr. Jauhar: For specialized surgery, you need the accrual of a certain amount of experience. The optimal age is about 60, because they’ve seen many things and they’ve seen complications. They don’t have a hand tremor yet so they’re still functioning well, and they’ve accrued a lot of experience. We have to be smart about who we screen.

There’s a learning curve in surgery. By no means am I arguing that younger surgeons are better surgeons. I would say that there’s probably a tipping point where once you get past a certain age and physical deterioration starts to take effect, that can overshadow the accrual of cognitive and surgical experience. We have to balance those things.

I would say neurocognitive screening and vision testing are important, but exactly what do you measure? How much of a hand tremor would constitute a risk? These things have to be figured out. I just want doctors to be leading the charge here and not have this imposed by bureaucrats.

Dr. Glatter: I was reading that some doctors have had these exams administered and they can really pass cognitive aspects of the exam, but there have been nuances in the actual practicing of medicine, day-to-day functioning, which they’re not good at.

Someone made a comment that the only way to know if a doctor can do well in practice is to observe their practice and observe them taking care of patients. In other words, you can game the system and pass the cognitive exam in some form but then have a problem practicing medicine.

Dr. Jauhar: Ultimately, outcomes have to be measured. We can’t adopt such a granular approach for every aging physician. There has to be some sort of screening that maybe raises a red flag and then hospitals and department chairs need to investigate further. What are the outcomes? What are people saying in the operating room? I think the screening is just that; it’s a way of opening the door to further investigation, but it’s not a witch hunt.

I have the highest respect for older physicians, and I learn from them every day, honestly, especially in my field (cardiology), because some of the older physicians can hear and see things on physical exam that I didn’t even know existed. There’s much to be learned from them.

This is not intended to be a witch hunt or to try to get rid of older physicians – by any means. We want to avoid some of the outcomes that I read about in the New York Times comments section. It’s not fair to our patients not to do at least some sort of screening to prevent those kinds of mistakes.

Dr. Glatter: I wanted to go back to data from Yale between October 2016 and January 2019, where 141 Yale clinicians who ranged in age from 69 to 92 years completed cognitive assessments. Of those, 18 clinicians, or about 13% of those tested, demonstrated cognitive deficits that were “deemed likely to impair their ability to practice medicine independently.” That’s telling. These are subtleties, but they’re important to identify. I would love to get your comment on that.

Dr. Jauhar: It’s in keeping with what we know about the proportion of our older citizens who have cognitive impairment. About 10% have dementia and about 20% have at least mild cognitive impairment. That’s in keeping with what we know, and this was a general screening.

There are certain programs, like in San Diego, for example, where physicians are referred, and so there’s a selection bias. But this was just general screening. It’s worrisome. I’m an aging physician myself. I want fairness in this process because I’m going to be assessed as well.

I just don’t really understand yet why there’s so much circling of the wagons and so much resistance. It seems like it would be good for physicians also to be removed from situations where they might get into potential litigation because of mistakes and physical or visual impairment. It seems like it’d be good for patients and physicians alike.

Dr. Glatter: It’s difficult to give up your profession, change fields, or become administrative at some point, and [decide] when to make that transition. As we all get older, we’re not going to have the ability to do what we did in our 20s, 30s, and so forth.

Dr. Jauhar: Much of the resistance is coming from doctors who are used to high levels of autonomy. I’m certainly sympathetic to that because I don’t want anyone telling me how to practice. The reason this is coming up and hasn’t come up in the past is not because of loss of autonomy but because of an actual demographic change. Many physicians were trained in the 1960s, ’70s, or ’80s. They’re getting to retirement age but they’re not retiring, and we can speculate as to why that is.

In America’s educational system, doctors incur a huge amount of debt. I know physicians who are still paying off their debt and they’re in their 50s and 60s, so I’m very sympathetic to that. I’m not trying to force doctors out of practicing. I just want whoever is practicing to be competent and to practice safely. We have to figure out how to do that.

Dr. Glatter: The fact that there is a shortage of physicians forecast in the next 10-15 years makes many physicians reluctant to retire. They feel like they want to be part of that support network and we don’t want to have a dire situation, especially in the rural areas. We’re not immune from aging. We’re human beings. We all have to realize that.

Dr. Jauhar: I know that the ACC is starting to debate this issue, in part because of my op-ed. My hope is that it will start a conversation and we will institute a plan that comes from physicians and serves our patients, and doesn’t serve some cottage industry of testing or serve the needs of insurers or bureaucrats. It has to serve the doctor-patient relationship.

Dr. Glatter: In some random surveys that I’ve read, up to 30%-40% of physicians do support some type of age-based screening or competency assessment. The needle’s moving. It’s just not there yet. I think that wider adoption is coming.

Dr. Jauhar: Data are coming as more hospitals start to adopt these late practitioner programs. Some of the data that came out of Yale, for example, are very important. We’re going to see more published data in this area, and it will clarify what we need to do and how big the problem is.

Dr. Glatter: I want to thank you again for your time and for writing the op-ed because it certainly was well read and opened the eyes of not only physicians, but also the public at large. It’s a conversation that has to be had. Thank you for doing this.

Dr. Jauhar: Thanks for inviting me, Robert. It was a pleasure to talk to you.

Dr. Glatter is assistant professor of emergency medicine, department of emergency medicine, at Hofstra University, Hempstead, N.Y. Dr. Jauhar is director of the heart failure program, Long Island Jewish Medical Center, New Hyde Park, N.Y. Neither Dr. Glatter nor Dr. Jauhar reported any relevant conflicts of interest.

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

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today is Sandeep Jauhar, a practicing cardiologist and professor of medicine at Northwell Health, a frequent New York Times op-ed contributor, and highly regarded author of the upcoming book “My Father’s Brain: Life in the Shadow of Alzheimer’s.”

We are here today to discuss the rationale for age competency exams for practicing physicians.

Sandeep Jauhar, MD: Thanks for having me.

Dr. Glatter: Your recent op-ed piece in the New York Times caught my eye. In your piece, you refer to a 2020 survey in which almost one-third of licensed doctors in the United States were 60 years of age or older, up from a quarter in 2010. You also state that, due to a 20% prevalence of mild cognitive impairment in persons older than 65, practicing physicians above this age should probably be screened by a battery of tests to ensure that their reasoning and cognitive abilities are intact. The title of the article is “How Would You Feel About a 100-Year-Old Doctor?”

How would you envision such a process? What aspects of day-to-day functioning would the exams truly be evaluating?

Dr. Jauhar: A significant number of people over 65 have measurable cognitive impairment. By cognitive impairment, we’re not talking about dementia. The best estimates are that 1 in 10 people over age 65 have dementia, and roughly 1 in 5 have what’s called MCI, or mild cognitive impairment, which is cognitive impairment out of proportion to what you’d expect from normal aging. It’s a significant issue.

The argument that I made in the op-ed is that neurocognitive assessment is important. That’s not to say that everyone over age 65 has significant cognitive impairment or that older doctors can’t practice medicine safely and effectively. They absolutely can. The question is, do we leave neurocognitive assessment to physicians who may possibly be suffering from impairment?

In dementia, people very often have impaired self-awareness, a condition called anosognosia, which is a neurological term for not being aware of your own impairment because of your impairment.

I would argue that, instead of having voluntary neurocognitive screening, it should be mandated. The question is how to do that effectively, fairly, and transparently.

One could argue a gerontocracy in medicine today, where there are so many older physicians. What do we do about that? That really is something that I think needs to be debated.

Dr. Glatter: The question I have is, if we (that is, physicians and the health care profession) don’t take care of this, someone’s going to do it for us. We need to jump on this now while we have the opportunity. The AMA has been opposed to this, except when you have reason to suspect cognitive decline or are concerned about patient safety. A mandatory age of retirement is certainly something they’re not for, and we know this.

Your argument in your op-ed piece is very well thought out, and you lay the groundwork for testing (looking at someone’s memory, coordination, processing speed, and other executive functions). Certainly, for a psychiatrist, hearing is important, and for a dermatologist, vision is important. For a surgeon, there are other issues. Based on the specialty, we must be careful to see the important aspects of functioning. I am sure you would agree with this.

Dr. Jauhar: Obviously, the hand skills that are important for ophthalmological surgery certainly aren’t required for office-based psychological counseling, for example. We have to be smart about how we assess impairment.

You describe the spectrum of actions. On the one hand, there’s mandatory retirement at the age of 65 or 70 years. We know that commercial pilots are mandated to essentially retire at 65, and air-traffic controllers must retire in their late 50s.

We know that there’s a large amount of variability in competence. There are internists in their 80s with whom I’ve worked, and I’m absolutely wowed by their experience and judgment. There are new medical resident graduates who don’t really seem to have the requisite level of competence that would make me feel comfortable to have them as my doctor or a doctor for a member of my family.

To mandate retirement, I think the AMA is absolutely right. To not call for any kind of competency testing, to me, seems equally unwise. Because at the end of the day, you have to balance individual physician needs or wants to continue practicing with patient safety. I haven’t really come across too many physicians who say, “There’s absolutely no need for a competency testing.”

We have to meet somewhere in the middle. The middle is either voluntary cognitive competency testing or mandatory. I would argue that, because we know that as the brain changes we have cognitive impairment, but we’re not always aware that we need help, mandatory testing is the way.

One other thing that you mentioned was about having the solution imposed on us. You and I are doctors. We deal with bureaucracy. We deal with poorly thought-out solutions to issues in health care that make our lives that much more difficult. I don’t want that solution imposed on us by some outside agency. I think we need to figure this out within medicine and figure out the right way of doing it.

The AMA is on board with this. They haven’t called for mandatory testing, but they have said that if testing were to occur, these are the guidelines. The guidelines are fair and equitable, not too time-consuming, transparent, and not punitive. If someone comes out and doesn’t test well, we shouldn’t force them out of the profession. We can find ways to use their experience to help train younger doctors, for example.

Dr. Glatter: I wanted to segue to an area where there has been some challenge to the legality of these mandatory types of age restrictions and imposing the exams as well. There’s been a lawsuit as well by the EEOC [Equal Employment Opportunity Commission], on behalf of Yale. Basically, there’s been a concern that ageism is part of what’s going on. Yale now screens their providers beginning at age 70, and they have a program. UCSD [University of California, San Diego] has a program in place. Obviously, these institutions are looking at it. This is a very small part of the overall picture.

Health care systems overall, we’re talking about a fraction of them in the country are really addressing the issue of competency exams. The question is, where do we go from here? How do we get engagement or adoption and get physicians as a whole to embrace this concept?

Dr. Jauhar: The EEOC filed a lawsuit on behalf of the Yale medical staff that argued that Yale’s plan to do vision testing and neurocognitive screening – there may be a physical exam also – constitutes age discrimination because it’s reserved for doctors over the age of 70. Those are the physicians who are most likely to have cognitive impairment.

We have rules already for impaired physicians who are, for example, addicted to illicit drugs or have alcohol abuse. We already have some of those measures in place. This is focused on cognitive impairment in aging physicians because cognitive impairment is an issue that arises with aging. We have to be clear about that.

Most younger physicians will not have measurable cognitive impairment that would impair their ability to practice. To force young physicians (for example, physicians in their forties) to undergo such screening, all in the name of preventing age discrimination, doesn’t strike me as being a good use of resources. They’re more likely to be false positives, as you know from Bayesian statistics. When you have low pretest probability, you’re more likely to get false positives.

How are we going to screen hundreds of thousands of physicians? We have to make a choice about the group that really is more likely to benefit from such screening. Very few hospitals are addressing this issue and it’s going to become more important.

Dr. Glatter: Surgeons have been particularly active in pushing for age-based screening. In 2016, the American College of Surgeons started making surgeons at age 65-70 undergo voluntary health and neurocognitive assessments, and encouraged physicians to disclose any concerning findings as part of their professional obligation, which is pretty impressive in my mind.

Surgeons’ skill set is quite demanding physically and technically. That the Society of Surgical Chairs took it upon themselves to institute this is pretty telling.

Dr. Jauhar: The overall society called for screening, but then in a separate survey of surgical chairs, the idea was advanced that we should have mandatory retirement. Now, I don’t particularly agree with that.

I’ve seen it, where you have the aging surgeon who was a star in their day, and no one wants to say anything when their skills have visibly degraded, and no one wants to carry that torch and tell them that they need to retire. What happens is people whisper, and unfortunately, bad outcomes have to occur before people tend to get involved, and that’s what I’m trying to prevent.

Dr. Glatter: The question is whether older physicians have worse patient outcomes. The evidence is inconclusive, but studies have shown higher mortality rates for cardiovascular surgeons in terms of the procedures that they do. On the flip side, there are also higher mortality rates for GI surgery performed by younger surgeons. It’s a mixed bag.

Dr. Jauhar: For specialized surgery, you need the accrual of a certain amount of experience. The optimal age is about 60, because they’ve seen many things and they’ve seen complications. They don’t have a hand tremor yet so they’re still functioning well, and they’ve accrued a lot of experience. We have to be smart about who we screen.

There’s a learning curve in surgery. By no means am I arguing that younger surgeons are better surgeons. I would say that there’s probably a tipping point where once you get past a certain age and physical deterioration starts to take effect, that can overshadow the accrual of cognitive and surgical experience. We have to balance those things.

I would say neurocognitive screening and vision testing are important, but exactly what do you measure? How much of a hand tremor would constitute a risk? These things have to be figured out. I just want doctors to be leading the charge here and not have this imposed by bureaucrats.

Dr. Glatter: I was reading that some doctors have had these exams administered and they can really pass cognitive aspects of the exam, but there have been nuances in the actual practicing of medicine, day-to-day functioning, which they’re not good at.

Someone made a comment that the only way to know if a doctor can do well in practice is to observe their practice and observe them taking care of patients. In other words, you can game the system and pass the cognitive exam in some form but then have a problem practicing medicine.

Dr. Jauhar: Ultimately, outcomes have to be measured. We can’t adopt such a granular approach for every aging physician. There has to be some sort of screening that maybe raises a red flag and then hospitals and department chairs need to investigate further. What are the outcomes? What are people saying in the operating room? I think the screening is just that; it’s a way of opening the door to further investigation, but it’s not a witch hunt.

I have the highest respect for older physicians, and I learn from them every day, honestly, especially in my field (cardiology), because some of the older physicians can hear and see things on physical exam that I didn’t even know existed. There’s much to be learned from them.

This is not intended to be a witch hunt or to try to get rid of older physicians – by any means. We want to avoid some of the outcomes that I read about in the New York Times comments section. It’s not fair to our patients not to do at least some sort of screening to prevent those kinds of mistakes.

Dr. Glatter: I wanted to go back to data from Yale between October 2016 and January 2019, where 141 Yale clinicians who ranged in age from 69 to 92 years completed cognitive assessments. Of those, 18 clinicians, or about 13% of those tested, demonstrated cognitive deficits that were “deemed likely to impair their ability to practice medicine independently.” That’s telling. These are subtleties, but they’re important to identify. I would love to get your comment on that.

Dr. Jauhar: It’s in keeping with what we know about the proportion of our older citizens who have cognitive impairment. About 10% have dementia and about 20% have at least mild cognitive impairment. That’s in keeping with what we know, and this was a general screening.

There are certain programs, like in San Diego, for example, where physicians are referred, and so there’s a selection bias. But this was just general screening. It’s worrisome. I’m an aging physician myself. I want fairness in this process because I’m going to be assessed as well.

I just don’t really understand yet why there’s so much circling of the wagons and so much resistance. It seems like it would be good for physicians also to be removed from situations where they might get into potential litigation because of mistakes and physical or visual impairment. It seems like it’d be good for patients and physicians alike.

Dr. Glatter: It’s difficult to give up your profession, change fields, or become administrative at some point, and [decide] when to make that transition. As we all get older, we’re not going to have the ability to do what we did in our 20s, 30s, and so forth.

Dr. Jauhar: Much of the resistance is coming from doctors who are used to high levels of autonomy. I’m certainly sympathetic to that because I don’t want anyone telling me how to practice. The reason this is coming up and hasn’t come up in the past is not because of loss of autonomy but because of an actual demographic change. Many physicians were trained in the 1960s, ’70s, or ’80s. They’re getting to retirement age but they’re not retiring, and we can speculate as to why that is.

In America’s educational system, doctors incur a huge amount of debt. I know physicians who are still paying off their debt and they’re in their 50s and 60s, so I’m very sympathetic to that. I’m not trying to force doctors out of practicing. I just want whoever is practicing to be competent and to practice safely. We have to figure out how to do that.

Dr. Glatter: The fact that there is a shortage of physicians forecast in the next 10-15 years makes many physicians reluctant to retire. They feel like they want to be part of that support network and we don’t want to have a dire situation, especially in the rural areas. We’re not immune from aging. We’re human beings. We all have to realize that.

Dr. Jauhar: I know that the ACC is starting to debate this issue, in part because of my op-ed. My hope is that it will start a conversation and we will institute a plan that comes from physicians and serves our patients, and doesn’t serve some cottage industry of testing or serve the needs of insurers or bureaucrats. It has to serve the doctor-patient relationship.

Dr. Glatter: In some random surveys that I’ve read, up to 30%-40% of physicians do support some type of age-based screening or competency assessment. The needle’s moving. It’s just not there yet. I think that wider adoption is coming.

Dr. Jauhar: Data are coming as more hospitals start to adopt these late practitioner programs. Some of the data that came out of Yale, for example, are very important. We’re going to see more published data in this area, and it will clarify what we need to do and how big the problem is.

Dr. Glatter: I want to thank you again for your time and for writing the op-ed because it certainly was well read and opened the eyes of not only physicians, but also the public at large. It’s a conversation that has to be had. Thank you for doing this.

Dr. Jauhar: Thanks for inviting me, Robert. It was a pleasure to talk to you.

Dr. Glatter is assistant professor of emergency medicine, department of emergency medicine, at Hofstra University, Hempstead, N.Y. Dr. Jauhar is director of the heart failure program, Long Island Jewish Medical Center, New Hyde Park, N.Y. Neither Dr. Glatter nor Dr. Jauhar reported any relevant conflicts of interest.

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

This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I’m Dr. Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today is Sandeep Jauhar, a practicing cardiologist and professor of medicine at Northwell Health, a frequent New York Times op-ed contributor, and highly regarded author of the upcoming book “My Father’s Brain: Life in the Shadow of Alzheimer’s.”

We are here today to discuss the rationale for age competency exams for practicing physicians.

Sandeep Jauhar, MD: Thanks for having me.

Dr. Glatter: Your recent op-ed piece in the New York Times caught my eye. In your piece, you refer to a 2020 survey in which almost one-third of licensed doctors in the United States were 60 years of age or older, up from a quarter in 2010. You also state that, due to a 20% prevalence of mild cognitive impairment in persons older than 65, practicing physicians above this age should probably be screened by a battery of tests to ensure that their reasoning and cognitive abilities are intact. The title of the article is “How Would You Feel About a 100-Year-Old Doctor?”

How would you envision such a process? What aspects of day-to-day functioning would the exams truly be evaluating?

Dr. Jauhar: A significant number of people over 65 have measurable cognitive impairment. By cognitive impairment, we’re not talking about dementia. The best estimates are that 1 in 10 people over age 65 have dementia, and roughly 1 in 5 have what’s called MCI, or mild cognitive impairment, which is cognitive impairment out of proportion to what you’d expect from normal aging. It’s a significant issue.

The argument that I made in the op-ed is that neurocognitive assessment is important. That’s not to say that everyone over age 65 has significant cognitive impairment or that older doctors can’t practice medicine safely and effectively. They absolutely can. The question is, do we leave neurocognitive assessment to physicians who may possibly be suffering from impairment?

In dementia, people very often have impaired self-awareness, a condition called anosognosia, which is a neurological term for not being aware of your own impairment because of your impairment.

I would argue that, instead of having voluntary neurocognitive screening, it should be mandated. The question is how to do that effectively, fairly, and transparently.

One could argue a gerontocracy in medicine today, where there are so many older physicians. What do we do about that? That really is something that I think needs to be debated.

Dr. Glatter: The question I have is, if we (that is, physicians and the health care profession) don’t take care of this, someone’s going to do it for us. We need to jump on this now while we have the opportunity. The AMA has been opposed to this, except when you have reason to suspect cognitive decline or are concerned about patient safety. A mandatory age of retirement is certainly something they’re not for, and we know this.

Your argument in your op-ed piece is very well thought out, and you lay the groundwork for testing (looking at someone’s memory, coordination, processing speed, and other executive functions). Certainly, for a psychiatrist, hearing is important, and for a dermatologist, vision is important. For a surgeon, there are other issues. Based on the specialty, we must be careful to see the important aspects of functioning. I am sure you would agree with this.

Dr. Jauhar: Obviously, the hand skills that are important for ophthalmological surgery certainly aren’t required for office-based psychological counseling, for example. We have to be smart about how we assess impairment.

You describe the spectrum of actions. On the one hand, there’s mandatory retirement at the age of 65 or 70 years. We know that commercial pilots are mandated to essentially retire at 65, and air-traffic controllers must retire in their late 50s.

We know that there’s a large amount of variability in competence. There are internists in their 80s with whom I’ve worked, and I’m absolutely wowed by their experience and judgment. There are new medical resident graduates who don’t really seem to have the requisite level of competence that would make me feel comfortable to have them as my doctor or a doctor for a member of my family.

To mandate retirement, I think the AMA is absolutely right. To not call for any kind of competency testing, to me, seems equally unwise. Because at the end of the day, you have to balance individual physician needs or wants to continue practicing with patient safety. I haven’t really come across too many physicians who say, “There’s absolutely no need for a competency testing.”

We have to meet somewhere in the middle. The middle is either voluntary cognitive competency testing or mandatory. I would argue that, because we know that as the brain changes we have cognitive impairment, but we’re not always aware that we need help, mandatory testing is the way.

One other thing that you mentioned was about having the solution imposed on us. You and I are doctors. We deal with bureaucracy. We deal with poorly thought-out solutions to issues in health care that make our lives that much more difficult. I don’t want that solution imposed on us by some outside agency. I think we need to figure this out within medicine and figure out the right way of doing it.

The AMA is on board with this. They haven’t called for mandatory testing, but they have said that if testing were to occur, these are the guidelines. The guidelines are fair and equitable, not too time-consuming, transparent, and not punitive. If someone comes out and doesn’t test well, we shouldn’t force them out of the profession. We can find ways to use their experience to help train younger doctors, for example.

Dr. Glatter: I wanted to segue to an area where there has been some challenge to the legality of these mandatory types of age restrictions and imposing the exams as well. There’s been a lawsuit as well by the EEOC [Equal Employment Opportunity Commission], on behalf of Yale. Basically, there’s been a concern that ageism is part of what’s going on. Yale now screens their providers beginning at age 70, and they have a program. UCSD [University of California, San Diego] has a program in place. Obviously, these institutions are looking at it. This is a very small part of the overall picture.

Health care systems overall, we’re talking about a fraction of them in the country are really addressing the issue of competency exams. The question is, where do we go from here? How do we get engagement or adoption and get physicians as a whole to embrace this concept?

Dr. Jauhar: The EEOC filed a lawsuit on behalf of the Yale medical staff that argued that Yale’s plan to do vision testing and neurocognitive screening – there may be a physical exam also – constitutes age discrimination because it’s reserved for doctors over the age of 70. Those are the physicians who are most likely to have cognitive impairment.

We have rules already for impaired physicians who are, for example, addicted to illicit drugs or have alcohol abuse. We already have some of those measures in place. This is focused on cognitive impairment in aging physicians because cognitive impairment is an issue that arises with aging. We have to be clear about that.

Most younger physicians will not have measurable cognitive impairment that would impair their ability to practice. To force young physicians (for example, physicians in their forties) to undergo such screening, all in the name of preventing age discrimination, doesn’t strike me as being a good use of resources. They’re more likely to be false positives, as you know from Bayesian statistics. When you have low pretest probability, you’re more likely to get false positives.

How are we going to screen hundreds of thousands of physicians? We have to make a choice about the group that really is more likely to benefit from such screening. Very few hospitals are addressing this issue and it’s going to become more important.

Dr. Glatter: Surgeons have been particularly active in pushing for age-based screening. In 2016, the American College of Surgeons started making surgeons at age 65-70 undergo voluntary health and neurocognitive assessments, and encouraged physicians to disclose any concerning findings as part of their professional obligation, which is pretty impressive in my mind.

Surgeons’ skill set is quite demanding physically and technically. That the Society of Surgical Chairs took it upon themselves to institute this is pretty telling.

Dr. Jauhar: The overall society called for screening, but then in a separate survey of surgical chairs, the idea was advanced that we should have mandatory retirement. Now, I don’t particularly agree with that.

I’ve seen it, where you have the aging surgeon who was a star in their day, and no one wants to say anything when their skills have visibly degraded, and no one wants to carry that torch and tell them that they need to retire. What happens is people whisper, and unfortunately, bad outcomes have to occur before people tend to get involved, and that’s what I’m trying to prevent.

Dr. Glatter: The question is whether older physicians have worse patient outcomes. The evidence is inconclusive, but studies have shown higher mortality rates for cardiovascular surgeons in terms of the procedures that they do. On the flip side, there are also higher mortality rates for GI surgery performed by younger surgeons. It’s a mixed bag.

Dr. Jauhar: For specialized surgery, you need the accrual of a certain amount of experience. The optimal age is about 60, because they’ve seen many things and they’ve seen complications. They don’t have a hand tremor yet so they’re still functioning well, and they’ve accrued a lot of experience. We have to be smart about who we screen.

There’s a learning curve in surgery. By no means am I arguing that younger surgeons are better surgeons. I would say that there’s probably a tipping point where once you get past a certain age and physical deterioration starts to take effect, that can overshadow the accrual of cognitive and surgical experience. We have to balance those things.

I would say neurocognitive screening and vision testing are important, but exactly what do you measure? How much of a hand tremor would constitute a risk? These things have to be figured out. I just want doctors to be leading the charge here and not have this imposed by bureaucrats.

Dr. Glatter: I was reading that some doctors have had these exams administered and they can really pass cognitive aspects of the exam, but there have been nuances in the actual practicing of medicine, day-to-day functioning, which they’re not good at.

Someone made a comment that the only way to know if a doctor can do well in practice is to observe their practice and observe them taking care of patients. In other words, you can game the system and pass the cognitive exam in some form but then have a problem practicing medicine.

Dr. Jauhar: Ultimately, outcomes have to be measured. We can’t adopt such a granular approach for every aging physician. There has to be some sort of screening that maybe raises a red flag and then hospitals and department chairs need to investigate further. What are the outcomes? What are people saying in the operating room? I think the screening is just that; it’s a way of opening the door to further investigation, but it’s not a witch hunt.

I have the highest respect for older physicians, and I learn from them every day, honestly, especially in my field (cardiology), because some of the older physicians can hear and see things on physical exam that I didn’t even know existed. There’s much to be learned from them.

This is not intended to be a witch hunt or to try to get rid of older physicians – by any means. We want to avoid some of the outcomes that I read about in the New York Times comments section. It’s not fair to our patients not to do at least some sort of screening to prevent those kinds of mistakes.

Dr. Glatter: I wanted to go back to data from Yale between October 2016 and January 2019, where 141 Yale clinicians who ranged in age from 69 to 92 years completed cognitive assessments. Of those, 18 clinicians, or about 13% of those tested, demonstrated cognitive deficits that were “deemed likely to impair their ability to practice medicine independently.” That’s telling. These are subtleties, but they’re important to identify. I would love to get your comment on that.

Dr. Jauhar: It’s in keeping with what we know about the proportion of our older citizens who have cognitive impairment. About 10% have dementia and about 20% have at least mild cognitive impairment. That’s in keeping with what we know, and this was a general screening.

There are certain programs, like in San Diego, for example, where physicians are referred, and so there’s a selection bias. But this was just general screening. It’s worrisome. I’m an aging physician myself. I want fairness in this process because I’m going to be assessed as well.

I just don’t really understand yet why there’s so much circling of the wagons and so much resistance. It seems like it would be good for physicians also to be removed from situations where they might get into potential litigation because of mistakes and physical or visual impairment. It seems like it’d be good for patients and physicians alike.

Dr. Glatter: It’s difficult to give up your profession, change fields, or become administrative at some point, and [decide] when to make that transition. As we all get older, we’re not going to have the ability to do what we did in our 20s, 30s, and so forth.

Dr. Jauhar: Much of the resistance is coming from doctors who are used to high levels of autonomy. I’m certainly sympathetic to that because I don’t want anyone telling me how to practice. The reason this is coming up and hasn’t come up in the past is not because of loss of autonomy but because of an actual demographic change. Many physicians were trained in the 1960s, ’70s, or ’80s. They’re getting to retirement age but they’re not retiring, and we can speculate as to why that is.

In America’s educational system, doctors incur a huge amount of debt. I know physicians who are still paying off their debt and they’re in their 50s and 60s, so I’m very sympathetic to that. I’m not trying to force doctors out of practicing. I just want whoever is practicing to be competent and to practice safely. We have to figure out how to do that.

Dr. Glatter: The fact that there is a shortage of physicians forecast in the next 10-15 years makes many physicians reluctant to retire. They feel like they want to be part of that support network and we don’t want to have a dire situation, especially in the rural areas. We’re not immune from aging. We’re human beings. We all have to realize that.

Dr. Jauhar: I know that the ACC is starting to debate this issue, in part because of my op-ed. My hope is that it will start a conversation and we will institute a plan that comes from physicians and serves our patients, and doesn’t serve some cottage industry of testing or serve the needs of insurers or bureaucrats. It has to serve the doctor-patient relationship.

Dr. Glatter: In some random surveys that I’ve read, up to 30%-40% of physicians do support some type of age-based screening or competency assessment. The needle’s moving. It’s just not there yet. I think that wider adoption is coming.

Dr. Jauhar: Data are coming as more hospitals start to adopt these late practitioner programs. Some of the data that came out of Yale, for example, are very important. We’re going to see more published data in this area, and it will clarify what we need to do and how big the problem is.

Dr. Glatter: I want to thank you again for your time and for writing the op-ed because it certainly was well read and opened the eyes of not only physicians, but also the public at large. It’s a conversation that has to be had. Thank you for doing this.

Dr. Jauhar: Thanks for inviting me, Robert. It was a pleasure to talk to you.

Dr. Glatter is assistant professor of emergency medicine, department of emergency medicine, at Hofstra University, Hempstead, N.Y. Dr. Jauhar is director of the heart failure program, Long Island Jewish Medical Center, New Hyde Park, N.Y. Neither Dr. Glatter nor Dr. Jauhar reported any relevant conflicts of interest.

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

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.

High levels of triglyceride molecules in LDL cholesterol are “robustly” linked with an increased risk of atherosclerotic cardiovascular disease, according to a study that used two different methods in two separate cohorts from a large European population study plus a meta-analysis to verify the results.

“There have been some studies in the past, as you can see from our meta-analysis, that found a similar association, but I don’t think most people are convinced that there is really this relationship, and certainly I was not convinced,” lead investigator Børge G. Nordestgaard, MD, DMSc, professor at the University of Copenhagen, said in an interview.

The study enrolled 68,290 patients from the Copenhagen General Population study; 38,081 were assigned to direct automated assay to measure their LDL triglycerides and 30,208 had nuclear magnetic resonance (NMR) spectroscopy. Median follow-up was 3 and 9.2 years for the respective cohorts.

LDL triglycerides carry higher ASCVD risk

In the automated assay group, each 0.1-mmol/L (9 mg/dL)–higher direct LDL triglycerides carried a 22%-38% higher risk for the following outcomes: ASCVD (hazard ratio, 1.26; 95% confidence interval, 1.17-1.35); ischemic heart disease (HR, 1.27; 95% CI, 1.16-1.39); myocardial infarction (HR, 1.28; 95% CI, 1.11-1.48); ischemic stroke (HR, 1.22; 95% CI, 1.08-1.38); and peripheral artery disease (HR, 1.38; 95% CI, 1.21-1.58).

In the group that had NMR spectroscopy to measure LDL triglycerides, risks were similar, ranging from HRs of 1.13 (95% CI, 1.05-1.23) for ischemic stroke to 1.41 (95% CI, 1.31-1.52) for myocardial infarction. The investigators noted that apolipoprotein B levels didn’t entirely explain these results.

The meta-analysis included 18 studies that evaluated varying cardiovascular disease outcomes. It compared random-effects risk ratios for the highest quartile vs. the lowest quartile of LDL triglycerides. They were 1.50 (95% CI, 1.35-1.66) for ASCVD (four studies, 71,526 individuals, 8,576 events); 1.62 (95% CI, 1.37-1.93) for ischemic heart disease (six studies, 107,538 individuals, 9,734 events); 1.30 (95% CI, 1.13-1.49) for ischemic stroke (four studies, 78,026 individuals, 4,273 events); and 1.53 (95% CI, 1.29-1.81) for peripheral artery disease (four studies, 107,511 individuals, 1,848 events). The study was published online in the Journal of the American College of Cardiology.

Results confirm hypothesis the study sought to disprove

The purpose of the study was to actually disprove the hypothesis that the study ended up confirming, Dr. Nordestgaard said. “When we started this study, my idea was that we wanted to show that LDL triglyceride was not related to these diseases, because that didn’t make sense to me,” he said. “I’m so used to the thinking that the cholesterol content of these particles drive atherosclerosis and therefore atherosclerotic cardiovascular disease.”

He noted that LDL can carry both cholesterol and triglycerides, and that larger remnant lipoproteins can carry a substantial amount of triglycerides and a lesser amount of cholesterol. “Those remnants actually transfer into LDL, so they somewhat bring the triglycerides molecules into LDL,” Dr. Nordestgaard said.

The direct automated assay test used in the study to measure LDL triglycerides is not approved for use in the United States by the Food and Drug Administration, according to Denka, the manufacturer of the test.

The use of the Copenhagen General Population Study cohorts is a strength of the study because it has 100% follow-up with all patients, Dr. Nordestgaard said. The meta-analysis is another strength. “So we can show real clearly, not only in our two prospective studies, but also added to the former ones in the literature: All say exactly the same thing: High LDL triglycerides carry a high risk for ASCVD and its components.”

A limitation Dr. Nordestgaard acknowledged: The study doesn’t explain the causal relationship between high LDL triglycerides and ASCVD. But the study provides “very sound evidence that there’s a relationship,” he added. The study population was also a White, Danish population that lacked ethnic and racial diversity.

Next step is finding a treatment

The Danish study essentially confirms what the Atherosclerosis Risk in Community Study (ARIC) found with regard to LDL triglycerides, said Christie M. Ballantyne, MD, chief of cardiology at Baylor College of Medicine in Houston, and an ARIC investigator. 

This study is the “first step” to coming up with a test to identify risk, he said. “These data are pretty convincing, when you throw in the data in this study plus all the meta-analyses data, that LDL triglycerides, when they’re elevated, identify individuals at increased risk for an atherosclerotic cardiovascular event.”

The next step, he said, is coming up with a treatment for people with elevated HDL triglyceride. “That’s where we don’t have as much data because this test hasn’t been used. I’m pretty sure that statins are going to work fine for these people, because they lower LDL cholesterol and they also lower triglycerides, and some of the data have shown already that they reduce the LDL remnant,” Dr. Ballantyne said.

The Danish study provides enough of a basis for pursuing future studies to better understand the effect of statins on LDL triglyceride levels, Dr. Ballantyne added.

The study received funding from the Novo Nordisk Foundation and the Danish Heart Foundation, along with institutional support. Dr. Nordestgaard has no relevant disclosures. Dr. Ballantyne disclosed receiving research support from Denka.