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Does EPA lower CV risk? REDUCE-IT revisited
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 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 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.
Early retirement and the terrible, horrible, no good, very bad cognitive decline
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.
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.
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!
- 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.
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.
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!
- 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.
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.
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!
- 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.
What to do when patients 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.
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.
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.
Telehealth parent-child interaction therapy improved behavior in children with developmental delay
The children received the therapy with their parents or caregivers, who were more likely to demonstrate positive parenting behaviors than parents in the control group, authors of the new research published in JAMA Pediatrics found.
Approximately 13% of children have some form of developmental delay (DD) and more than half of these children also have at least one mental health disorder, which makes behavior problems a common and ongoing challenge, Daniel M. Bagner, PhD, a psychologist at Florida International University, Miami, and colleagues wrote.
Clinic-based interventions such as parent-child interaction therapy (PCIT) have been effective for improving behavior in children with DD, the researchers said. PCIT involves in-session caregiver coaching using a 1-way mirror and a wireless earpiece worn by the caregiver.
Barriers to the use of PCIT, especially in marginalized and low-income communities, include transportation, clinician shortages, and stigma-related concerns about a clinic visit, the researchers wrote. Technology now allows for Internet-delivered PCIT to reach more children and families, but its effectiveness for children with DD has not been well studied.
In the new study, the researchers randomized 150 children with DD and externalizing behavior problems to up to 20 weeks of Internet-delivered parent-child interaction therapy (iPCIT) or to referral as usual (RAU, the control group). The children were randomized after completion of early intervention services within 3 months of their third birthday, and participated in the sessions with a parent or caregiver. Most of the participants were from economically disadvantaged households and underrepresented ethnic backgrounds.
The iPCIT intervention was conducted weekly with a remote therapist and lasted for 1-1.5 hours; approximately half of the families received the intervention in Spanish.
The primary outcome was rating on the Child Behavior Checklist (CBCL) and assessment of children and caregivers using the Dyadic Parent-Child Interaction Coding System, fourth edition (DPICS). Assessments occurred at baseline and at week 20 (post treatment), with follow ups at 6 and 12 months.
Scores on the CBCL in the iPCIT group decreased from a mean of 61.18 at baseline to 53.83 post intervention. Scores for the control group started at 64.05 and decreased to 59.49 post intervention. At 6-12 months, the scores for both groups remained stable.
Children who received iPCIT with their parent or caregiver also showed significantly lower levels of externalizing behavior problems, compared with the RAU controls post treatment, and at 6-month and 12-month follow-ups based on the Cohen d measure of standardized effect size for differences between groups.
Significantly more children in the iPCIT group showed clinically significant improvements in externalizing problems at post treatment, compared with the RAU group (74% vs. 42%; P < .001) and at 6 months’ follow-up (73% vs. 45%; P = .002). However, the differences from baseline were not significantly different between the two groups after 12 months, which suggests that the effects may wane over time, the researchers noted.
In addition, the rate of child compliance with parent commands, as measured by a cleanup task, approximately doubled by the 12-month follow-up among children in the iPCIT group versus an increase of approximately one-third in the RAU group.
For secondary outcome measures related to caregiver behaviors, the proportion of observed positive parenting behaviors increased in the iPCIT group during the course of the intervention (postintervention odds ratio, 1.10), and the proportion of controlling and critical behaviors decreased (postintervention OR, 1.40). Harsh and inconsistent discipline decreased in both groups based on self-reports, but the decrease was steeper in iPCIT families.
iPCIT did not have a greater impact than RAU in reducing caregiver stress. The researchers wrote that they were not surprised by the lack of stress reduction “given mixed findings on the impact of parenting interventions on stress in caregivers of children with DD.”
Data support iPCIT potential
Overall, the results support findings from previous studies of clinic-based PCIT for children with DD and previous studies of telehealth interventions for typically developing children, the researchers said.
“Moreover, iPCIT-treated children not only showed reductions in behavior problems, such as aggression, but demonstrated higher rates of following directions, which is especially important for children entering kindergarten,” they wrote.
The findings were limited by several factors including the narrow focus on the primary and secondary outcomes, the use of data from a single site in a single metropolitan area – which may limit generalizability – and the lack of comparison between iPCIT and a clinic-based PCIT control group, the researchers noted. The equipment in the current study was provided to families; therefore, differences in treatment response could not be attributed to differences in technology.
The study represents the first known randomized controlled trial to evaluate a telehealth parenting intervention for children with, according to the researchers. The results suggest that technology can be leveraged to help these patients, including those from ethnic minority families who may be underserved by clinic-based care in overcoming barriers to treatment such as transportation and availability of clinicians. Use of iPCIT could be a critical resource as young children with DD complete Part C services and enter the school system.
Practical pediatric takeaways
“This was a great study, well-designed and very important and helpful for pediatric providers,” Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Young children with developmental delay and/or mental and behavioral health disorders require early identification and intervention,” said Dr. Haut. However, obstacles to intervention include stigma or parental denial of the disorder, as well as more practical challenges related to transportation, time to access a clinic or office, potential long length of treatment, and cost.
“Despite availability of state programs for young children, follow up and continued services can be challenging to complete. Once the child outgrows the state program finding alternative therapy can be difficult with the current shortage of pediatric mental health providers,” Dr. Haut noted.
“I was surprised to see that this study treatment phase was completed prior to the COVID-19 pandemic, when telehealth was not as popular a mode for health care and was not utilized to the extent that it is now, especially for pediatric care,” said Dr. Haut. “I was not surprised at the results, as the traditional mode of PCIT includes therapy and training in a space that may not be as familiar to the child as their home environment, and would include live presence of the therapist/s, which may add to anxiety for both the parent and child.”
That almost half of the parents participating in the study had graduated from college and/or completed graduate degrees “may have contributed to some of the success of this study,” Dr. Haut noted.
Benefits and barriers
“The COVID-19 pandemic brought significant change to the frequency of use and overall success of telehealth services,” Dr. Haut said. “Additional provider education in aspects such as provider technique and the use of medical devices with improved specific health care technology assisted in advancing the experience and opportunity for successful telehealth visits. Telehealth therapy offers a cost-effective option for any pediatric patients and for providers, as the time and space commitment for the patient visit can be considerably less than live office visits.
“Unfortunately, there are still overall barriers that I have personally experienced with telehealth, including interruptions in connectivity, background noise, and lack of an available computer or tablet; and with the use of cell phones not always allowing full inclusion of the caregiver and child,” said Dr. Haut. Children with DD, behavioral problems, or other mental health disorders may pose challenges for parents to manage at home while simultaneously trying to fully focus on the therapy in an online setting.
Although the current study is encouraging, “larger studies focused on specific or individual pediatric mental health and/or behavioral disorders may offer more information for providers, and better document the success of telehealth delivery of services,” Dr. Haut said.
The study was supported by the National Institute of Child Health and Human Development. Dr. Bagner disclosed funding from the National Institutes of Health. He also disclosed personal fees from PCIT International to train clinicians in PCIT supported by a grant from the Florida Department of Children and Families outside the current study. Dr. Haut had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.
The children received the therapy with their parents or caregivers, who were more likely to demonstrate positive parenting behaviors than parents in the control group, authors of the new research published in JAMA Pediatrics found.
Approximately 13% of children have some form of developmental delay (DD) and more than half of these children also have at least one mental health disorder, which makes behavior problems a common and ongoing challenge, Daniel M. Bagner, PhD, a psychologist at Florida International University, Miami, and colleagues wrote.
Clinic-based interventions such as parent-child interaction therapy (PCIT) have been effective for improving behavior in children with DD, the researchers said. PCIT involves in-session caregiver coaching using a 1-way mirror and a wireless earpiece worn by the caregiver.
Barriers to the use of PCIT, especially in marginalized and low-income communities, include transportation, clinician shortages, and stigma-related concerns about a clinic visit, the researchers wrote. Technology now allows for Internet-delivered PCIT to reach more children and families, but its effectiveness for children with DD has not been well studied.
In the new study, the researchers randomized 150 children with DD and externalizing behavior problems to up to 20 weeks of Internet-delivered parent-child interaction therapy (iPCIT) or to referral as usual (RAU, the control group). The children were randomized after completion of early intervention services within 3 months of their third birthday, and participated in the sessions with a parent or caregiver. Most of the participants were from economically disadvantaged households and underrepresented ethnic backgrounds.
The iPCIT intervention was conducted weekly with a remote therapist and lasted for 1-1.5 hours; approximately half of the families received the intervention in Spanish.
The primary outcome was rating on the Child Behavior Checklist (CBCL) and assessment of children and caregivers using the Dyadic Parent-Child Interaction Coding System, fourth edition (DPICS). Assessments occurred at baseline and at week 20 (post treatment), with follow ups at 6 and 12 months.
Scores on the CBCL in the iPCIT group decreased from a mean of 61.18 at baseline to 53.83 post intervention. Scores for the control group started at 64.05 and decreased to 59.49 post intervention. At 6-12 months, the scores for both groups remained stable.
Children who received iPCIT with their parent or caregiver also showed significantly lower levels of externalizing behavior problems, compared with the RAU controls post treatment, and at 6-month and 12-month follow-ups based on the Cohen d measure of standardized effect size for differences between groups.
Significantly more children in the iPCIT group showed clinically significant improvements in externalizing problems at post treatment, compared with the RAU group (74% vs. 42%; P < .001) and at 6 months’ follow-up (73% vs. 45%; P = .002). However, the differences from baseline were not significantly different between the two groups after 12 months, which suggests that the effects may wane over time, the researchers noted.
In addition, the rate of child compliance with parent commands, as measured by a cleanup task, approximately doubled by the 12-month follow-up among children in the iPCIT group versus an increase of approximately one-third in the RAU group.
For secondary outcome measures related to caregiver behaviors, the proportion of observed positive parenting behaviors increased in the iPCIT group during the course of the intervention (postintervention odds ratio, 1.10), and the proportion of controlling and critical behaviors decreased (postintervention OR, 1.40). Harsh and inconsistent discipline decreased in both groups based on self-reports, but the decrease was steeper in iPCIT families.
iPCIT did not have a greater impact than RAU in reducing caregiver stress. The researchers wrote that they were not surprised by the lack of stress reduction “given mixed findings on the impact of parenting interventions on stress in caregivers of children with DD.”
Data support iPCIT potential
Overall, the results support findings from previous studies of clinic-based PCIT for children with DD and previous studies of telehealth interventions for typically developing children, the researchers said.
“Moreover, iPCIT-treated children not only showed reductions in behavior problems, such as aggression, but demonstrated higher rates of following directions, which is especially important for children entering kindergarten,” they wrote.
The findings were limited by several factors including the narrow focus on the primary and secondary outcomes, the use of data from a single site in a single metropolitan area – which may limit generalizability – and the lack of comparison between iPCIT and a clinic-based PCIT control group, the researchers noted. The equipment in the current study was provided to families; therefore, differences in treatment response could not be attributed to differences in technology.
The study represents the first known randomized controlled trial to evaluate a telehealth parenting intervention for children with, according to the researchers. The results suggest that technology can be leveraged to help these patients, including those from ethnic minority families who may be underserved by clinic-based care in overcoming barriers to treatment such as transportation and availability of clinicians. Use of iPCIT could be a critical resource as young children with DD complete Part C services and enter the school system.
Practical pediatric takeaways
“This was a great study, well-designed and very important and helpful for pediatric providers,” Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Young children with developmental delay and/or mental and behavioral health disorders require early identification and intervention,” said Dr. Haut. However, obstacles to intervention include stigma or parental denial of the disorder, as well as more practical challenges related to transportation, time to access a clinic or office, potential long length of treatment, and cost.
“Despite availability of state programs for young children, follow up and continued services can be challenging to complete. Once the child outgrows the state program finding alternative therapy can be difficult with the current shortage of pediatric mental health providers,” Dr. Haut noted.
“I was surprised to see that this study treatment phase was completed prior to the COVID-19 pandemic, when telehealth was not as popular a mode for health care and was not utilized to the extent that it is now, especially for pediatric care,” said Dr. Haut. “I was not surprised at the results, as the traditional mode of PCIT includes therapy and training in a space that may not be as familiar to the child as their home environment, and would include live presence of the therapist/s, which may add to anxiety for both the parent and child.”
That almost half of the parents participating in the study had graduated from college and/or completed graduate degrees “may have contributed to some of the success of this study,” Dr. Haut noted.
Benefits and barriers
“The COVID-19 pandemic brought significant change to the frequency of use and overall success of telehealth services,” Dr. Haut said. “Additional provider education in aspects such as provider technique and the use of medical devices with improved specific health care technology assisted in advancing the experience and opportunity for successful telehealth visits. Telehealth therapy offers a cost-effective option for any pediatric patients and for providers, as the time and space commitment for the patient visit can be considerably less than live office visits.
“Unfortunately, there are still overall barriers that I have personally experienced with telehealth, including interruptions in connectivity, background noise, and lack of an available computer or tablet; and with the use of cell phones not always allowing full inclusion of the caregiver and child,” said Dr. Haut. Children with DD, behavioral problems, or other mental health disorders may pose challenges for parents to manage at home while simultaneously trying to fully focus on the therapy in an online setting.
Although the current study is encouraging, “larger studies focused on specific or individual pediatric mental health and/or behavioral disorders may offer more information for providers, and better document the success of telehealth delivery of services,” Dr. Haut said.
The study was supported by the National Institute of Child Health and Human Development. Dr. Bagner disclosed funding from the National Institutes of Health. He also disclosed personal fees from PCIT International to train clinicians in PCIT supported by a grant from the Florida Department of Children and Families outside the current study. Dr. Haut had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.
The children received the therapy with their parents or caregivers, who were more likely to demonstrate positive parenting behaviors than parents in the control group, authors of the new research published in JAMA Pediatrics found.
Approximately 13% of children have some form of developmental delay (DD) and more than half of these children also have at least one mental health disorder, which makes behavior problems a common and ongoing challenge, Daniel M. Bagner, PhD, a psychologist at Florida International University, Miami, and colleagues wrote.
Clinic-based interventions such as parent-child interaction therapy (PCIT) have been effective for improving behavior in children with DD, the researchers said. PCIT involves in-session caregiver coaching using a 1-way mirror and a wireless earpiece worn by the caregiver.
Barriers to the use of PCIT, especially in marginalized and low-income communities, include transportation, clinician shortages, and stigma-related concerns about a clinic visit, the researchers wrote. Technology now allows for Internet-delivered PCIT to reach more children and families, but its effectiveness for children with DD has not been well studied.
In the new study, the researchers randomized 150 children with DD and externalizing behavior problems to up to 20 weeks of Internet-delivered parent-child interaction therapy (iPCIT) or to referral as usual (RAU, the control group). The children were randomized after completion of early intervention services within 3 months of their third birthday, and participated in the sessions with a parent or caregiver. Most of the participants were from economically disadvantaged households and underrepresented ethnic backgrounds.
The iPCIT intervention was conducted weekly with a remote therapist and lasted for 1-1.5 hours; approximately half of the families received the intervention in Spanish.
The primary outcome was rating on the Child Behavior Checklist (CBCL) and assessment of children and caregivers using the Dyadic Parent-Child Interaction Coding System, fourth edition (DPICS). Assessments occurred at baseline and at week 20 (post treatment), with follow ups at 6 and 12 months.
Scores on the CBCL in the iPCIT group decreased from a mean of 61.18 at baseline to 53.83 post intervention. Scores for the control group started at 64.05 and decreased to 59.49 post intervention. At 6-12 months, the scores for both groups remained stable.
Children who received iPCIT with their parent or caregiver also showed significantly lower levels of externalizing behavior problems, compared with the RAU controls post treatment, and at 6-month and 12-month follow-ups based on the Cohen d measure of standardized effect size for differences between groups.
Significantly more children in the iPCIT group showed clinically significant improvements in externalizing problems at post treatment, compared with the RAU group (74% vs. 42%; P < .001) and at 6 months’ follow-up (73% vs. 45%; P = .002). However, the differences from baseline were not significantly different between the two groups after 12 months, which suggests that the effects may wane over time, the researchers noted.
In addition, the rate of child compliance with parent commands, as measured by a cleanup task, approximately doubled by the 12-month follow-up among children in the iPCIT group versus an increase of approximately one-third in the RAU group.
For secondary outcome measures related to caregiver behaviors, the proportion of observed positive parenting behaviors increased in the iPCIT group during the course of the intervention (postintervention odds ratio, 1.10), and the proportion of controlling and critical behaviors decreased (postintervention OR, 1.40). Harsh and inconsistent discipline decreased in both groups based on self-reports, but the decrease was steeper in iPCIT families.
iPCIT did not have a greater impact than RAU in reducing caregiver stress. The researchers wrote that they were not surprised by the lack of stress reduction “given mixed findings on the impact of parenting interventions on stress in caregivers of children with DD.”
Data support iPCIT potential
Overall, the results support findings from previous studies of clinic-based PCIT for children with DD and previous studies of telehealth interventions for typically developing children, the researchers said.
“Moreover, iPCIT-treated children not only showed reductions in behavior problems, such as aggression, but demonstrated higher rates of following directions, which is especially important for children entering kindergarten,” they wrote.
The findings were limited by several factors including the narrow focus on the primary and secondary outcomes, the use of data from a single site in a single metropolitan area – which may limit generalizability – and the lack of comparison between iPCIT and a clinic-based PCIT control group, the researchers noted. The equipment in the current study was provided to families; therefore, differences in treatment response could not be attributed to differences in technology.
The study represents the first known randomized controlled trial to evaluate a telehealth parenting intervention for children with, according to the researchers. The results suggest that technology can be leveraged to help these patients, including those from ethnic minority families who may be underserved by clinic-based care in overcoming barriers to treatment such as transportation and availability of clinicians. Use of iPCIT could be a critical resource as young children with DD complete Part C services and enter the school system.
Practical pediatric takeaways
“This was a great study, well-designed and very important and helpful for pediatric providers,” Cathy Haut, DNP, CPNP-AC, CPNP-PC, a pediatric nurse practitioner in Rehoboth Beach, Del., said in an interview.
“Young children with developmental delay and/or mental and behavioral health disorders require early identification and intervention,” said Dr. Haut. However, obstacles to intervention include stigma or parental denial of the disorder, as well as more practical challenges related to transportation, time to access a clinic or office, potential long length of treatment, and cost.
“Despite availability of state programs for young children, follow up and continued services can be challenging to complete. Once the child outgrows the state program finding alternative therapy can be difficult with the current shortage of pediatric mental health providers,” Dr. Haut noted.
“I was surprised to see that this study treatment phase was completed prior to the COVID-19 pandemic, when telehealth was not as popular a mode for health care and was not utilized to the extent that it is now, especially for pediatric care,” said Dr. Haut. “I was not surprised at the results, as the traditional mode of PCIT includes therapy and training in a space that may not be as familiar to the child as their home environment, and would include live presence of the therapist/s, which may add to anxiety for both the parent and child.”
That almost half of the parents participating in the study had graduated from college and/or completed graduate degrees “may have contributed to some of the success of this study,” Dr. Haut noted.
Benefits and barriers
“The COVID-19 pandemic brought significant change to the frequency of use and overall success of telehealth services,” Dr. Haut said. “Additional provider education in aspects such as provider technique and the use of medical devices with improved specific health care technology assisted in advancing the experience and opportunity for successful telehealth visits. Telehealth therapy offers a cost-effective option for any pediatric patients and for providers, as the time and space commitment for the patient visit can be considerably less than live office visits.
“Unfortunately, there are still overall barriers that I have personally experienced with telehealth, including interruptions in connectivity, background noise, and lack of an available computer or tablet; and with the use of cell phones not always allowing full inclusion of the caregiver and child,” said Dr. Haut. Children with DD, behavioral problems, or other mental health disorders may pose challenges for parents to manage at home while simultaneously trying to fully focus on the therapy in an online setting.
Although the current study is encouraging, “larger studies focused on specific or individual pediatric mental health and/or behavioral disorders may offer more information for providers, and better document the success of telehealth delivery of services,” Dr. Haut said.
The study was supported by the National Institute of Child Health and Human Development. Dr. Bagner disclosed funding from the National Institutes of Health. He also disclosed personal fees from PCIT International to train clinicians in PCIT supported by a grant from the Florida Department of Children and Families outside the current study. Dr. Haut had no financial conflicts to disclose, but serves on the editorial advisory board of Pediatric News.
FROM JAMA PEDIATRICS
New Omicron subvariant is ‘crazy infectious,’ COVID expert warns
“It’s crazy infectious,” said Paula Cannon, PhD, a virologist at the University of Southern California, Los Angeles. “All the things that have protected you for the past couple of years, I don’t think are going to protect you against this new crop of variants.”
XBB.1.5 is spreading quickly in the United States. It accounted for 27.6% of cases in the country in the week ending on Jan. 7, up from about 1% of cases at one point in December, according to the Centers for Disease Control and Prevention. It’s especially prevalent in the Northeast, now accounting for more than 70% of the cases in that region.
It’s spreading across the globe, too. Maria Van Kerkhove, PhD, technical lead of the World Health Organization, has called XBB.1.5 is “the most transmissible subvariant that has been detected yet.”
Ashish Jha, MD, the White House COVID-19 response coordinator, tweeted a few days ago that the spread of XBB.1.5 is “stunning” but cautioned that it’s unclear if the symptoms of infection will be more severe than for previous variants.
“Whether we’ll have an XBB.1.5 wave (and if yes, how big) will depend on many factors including immunity of the population, people’s actions, etc.,” he tweeted.
He urged people to get up to date on their boosters, wear a snug-fitting mask, and avoid crowded indoor spaces. He noted that people who haven’t been infected recently or haven’t gotten the bivalent booster likely have little protection against infection.
The symptoms for XBB.1.5 appear to be the same as for other versions of COVID-19. However, it’s less common for people infected with XBB.1.5 to report losing their sense of taste and smell, USA Today reported.
A version of this article first appeared on WebMD.com.
“It’s crazy infectious,” said Paula Cannon, PhD, a virologist at the University of Southern California, Los Angeles. “All the things that have protected you for the past couple of years, I don’t think are going to protect you against this new crop of variants.”
XBB.1.5 is spreading quickly in the United States. It accounted for 27.6% of cases in the country in the week ending on Jan. 7, up from about 1% of cases at one point in December, according to the Centers for Disease Control and Prevention. It’s especially prevalent in the Northeast, now accounting for more than 70% of the cases in that region.
It’s spreading across the globe, too. Maria Van Kerkhove, PhD, technical lead of the World Health Organization, has called XBB.1.5 is “the most transmissible subvariant that has been detected yet.”
Ashish Jha, MD, the White House COVID-19 response coordinator, tweeted a few days ago that the spread of XBB.1.5 is “stunning” but cautioned that it’s unclear if the symptoms of infection will be more severe than for previous variants.
“Whether we’ll have an XBB.1.5 wave (and if yes, how big) will depend on many factors including immunity of the population, people’s actions, etc.,” he tweeted.
He urged people to get up to date on their boosters, wear a snug-fitting mask, and avoid crowded indoor spaces. He noted that people who haven’t been infected recently or haven’t gotten the bivalent booster likely have little protection against infection.
The symptoms for XBB.1.5 appear to be the same as for other versions of COVID-19. However, it’s less common for people infected with XBB.1.5 to report losing their sense of taste and smell, USA Today reported.
A version of this article first appeared on WebMD.com.
“It’s crazy infectious,” said Paula Cannon, PhD, a virologist at the University of Southern California, Los Angeles. “All the things that have protected you for the past couple of years, I don’t think are going to protect you against this new crop of variants.”
XBB.1.5 is spreading quickly in the United States. It accounted for 27.6% of cases in the country in the week ending on Jan. 7, up from about 1% of cases at one point in December, according to the Centers for Disease Control and Prevention. It’s especially prevalent in the Northeast, now accounting for more than 70% of the cases in that region.
It’s spreading across the globe, too. Maria Van Kerkhove, PhD, technical lead of the World Health Organization, has called XBB.1.5 is “the most transmissible subvariant that has been detected yet.”
Ashish Jha, MD, the White House COVID-19 response coordinator, tweeted a few days ago that the spread of XBB.1.5 is “stunning” but cautioned that it’s unclear if the symptoms of infection will be more severe than for previous variants.
“Whether we’ll have an XBB.1.5 wave (and if yes, how big) will depend on many factors including immunity of the population, people’s actions, etc.,” he tweeted.
He urged people to get up to date on their boosters, wear a snug-fitting mask, and avoid crowded indoor spaces. He noted that people who haven’t been infected recently or haven’t gotten the bivalent booster likely have little protection against infection.
The symptoms for XBB.1.5 appear to be the same as for other versions of COVID-19. However, it’s less common for people infected with XBB.1.5 to report losing their sense of taste and smell, USA Today reported.
A version of this article first appeared on WebMD.com.
What to know about newly approved Alzheimer’s drug
, offering hope where there has been little for patients and their families affected by the devastating disease.
More than 6 million people in the United States live with Alzheimer’s.
It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.
But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”
Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.
So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
What does the FDA action mean?
The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.
The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.
With the FDA approval in hand, doctors can now prescribe the medication.
Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.
“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”
The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
Potential benefit?
Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.
Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
Concerns about side effects
The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.
Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.
Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.
“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.
The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.
“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.
Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”
The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
How much will it cost?
Eisai says that lecanemab will cost $26,500 a year.
In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.
An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
Will Medicare cover it?
The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.
That means people would have to pay thousands out of pocket at first to get it.
The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.
On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.
CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”
“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
Who benefits most from this drug?
Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.
Who makes lecanemab?
Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.
What’s the Alzheimer’s Association’s view?
The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.
It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”
“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
Are there alternatives?
The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.
Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.
A version of this article first appeared on WebMD.com.
, offering hope where there has been little for patients and their families affected by the devastating disease.
More than 6 million people in the United States live with Alzheimer’s.
It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.
But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”
Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.
So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
What does the FDA action mean?
The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.
The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.
With the FDA approval in hand, doctors can now prescribe the medication.
Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.
“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”
The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
Potential benefit?
Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.
Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
Concerns about side effects
The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.
Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.
Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.
“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.
The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.
“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.
Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”
The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
How much will it cost?
Eisai says that lecanemab will cost $26,500 a year.
In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.
An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
Will Medicare cover it?
The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.
That means people would have to pay thousands out of pocket at first to get it.
The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.
On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.
CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”
“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
Who benefits most from this drug?
Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.
Who makes lecanemab?
Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.
What’s the Alzheimer’s Association’s view?
The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.
It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”
“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
Are there alternatives?
The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.
Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.
A version of this article first appeared on WebMD.com.
, offering hope where there has been little for patients and their families affected by the devastating disease.
More than 6 million people in the United States live with Alzheimer’s.
It’s not a cure, but the drug, given intravenously every 2 weeks, has shown moderate positive effects in clinical trials in slowing early-stage disease.
But many are wary. As explained in an editorial in the journal The Lancet, “The Alzheimer’s disease community has become accustomed to false hope, disappointment, and controversy.”
Some worry about lecanemab’s safety as some people in clinical trials experienced serious side effects of bleeding and swelling in the brain. Scientists recently attributed a third death to lecanemab, brand name Leqembi, though the drugmaker disputed the medication was the cause.
So what should patients and their families make of this news? Here we answer some of the top questions surrounding the drug.
What does the FDA action mean?
The FDA granted accelerated approval to Leqembi after it showed positive trial results in slowing the progression of early-stage disease.
The FDA can grant accelerated approval for drugs that treat serious conditions and fill an unmet medical need while drugs continue to be studied in larger trials.
With the FDA approval in hand, doctors can now prescribe the medication.
Rebecca Edelmayer, PhD, the Alzheimer’s Association senior director of scientific engagement, says that with the FDA’s move, ramping up manufacturing – and eventually nationwide distribution and implementation – will take some time.
“Ask your doctor about availability,” she says. “The main issue is that, without insurance and Medicare coverage of this class of treatments, access for those who could benefit from the newly approved treatment will only be available to those who can pay out-of-pocket. Without coverage, people simply won’t be able to get the treatment.”
The Washington Post reports that with accelerated approval, drugmaker Eisai is expected to immediately apply for full FDA approval, which wouldn’t be likely to come before later this year. Full approval could help clear the path for Medicare coverage of the drug.
Potential benefit?
Those who got Leqembi in a clinical trial for 18 months experienced 27% less decline in memory and thinking relative to the group who got a placebo. It also reduced amyloid in the brain, the sticky protein that builds up in the brains of people with Alzheimer’s and is considered a hallmark of the disease.
Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation, says, “It’s the first phase 3 study in our field of a disease-modifying drug where the clinical efficacy was very clear.”
Concerns about side effects
The drug has raised safety concerns as it has been linked with certain serious adverse events, including brain swelling and bleeding. In the trial, 14% of patients who received the drug experienced side effects that included brain swelling and bleeding, compared with about 11% in the placebo group.
Scientists have reportedly linked three deaths during the clinical trial to lecanemab, though it is unclear whether it caused the deaths.
Dr. Fillit notes that the first two people who died were on blood thinners when they received lecanemab.
“There are things about the use of the drug in the real world that we need to work out, especially in the context of people with comorbidities,” he says.
The third death is a little different, Dr. Fillit says. The patient, who had a stroke, showed signs of vasculitis, or inflammation of the blood vessels.
“We don’t know exactly what happened, but we do know it was very, very rare” among the people involved in the trials, he says.
Dr. Edelmayer says that the most common reported side effects during the trials were infusion-related reactions, headache, and amyloid-related imaging abnormalities (ARIA). According to the FDA, these abnormalities “are known to occur with antibodies of this class. ARIA usually does not have symptoms, although serious and life-threatening events rarely may occur.”
The FDA has added these as warnings to the drug’s label, describing the possible infusion-related reactions as flu-like symptoms, nausea, vomiting, and changes in blood pressure.
How much will it cost?
Eisai says that lecanemab will cost $26,500 a year.
In a draft report released in December, the Institute for Clinical and Economic Review said a price ranging from $8,500 to $20,600 a year would make the drug cost-effective. While the group has no authority to set prices, many large health insurers consider its reports when they negotiate prices and some drugmakers take into account ICER’s recommendations when setting prices.
An editorial in The Lancet last month warns that the cost will likely be “prohibitive” for low- and middle-income countries and many health systems don’t have the infrastructure for a widespread rollout.
Will Medicare cover it?
The Centers for Medicare & Medicaid Services, which runs Medicare, which covers most people with Alzheimer’s, has indicated it won’t broadly cover amyloid-lowering drugs until the drug gets full U.S. approval based on clinical benefits, as opposed to accelerated approval.
That means people would have to pay thousands out of pocket at first to get it.
The CMS decision effectively denies Medicare coverage of fast-tracked FDA-approved medications for Alzheimer’s disease unless the person is enrolled in an approved clinical trial.
On Dec. 19, the Alzheimer’s Association filed a formal request asking CMS to remove the trial-only requirement and provide full and unrestricted coverage for FDA-approved Alzheimer’s treatments.
CMS says in a statement issued after the announcement: “Because Eisai’s product, lecanemab, was granted accelerated approval by the FDA, it falls under CMS’s existing national coverage determination. CMS is examining available information and may reconsider its current coverage based on this review.”
“If lecanemab subsequently receives traditional FDA approval, CMS would provide broader coverage,” the statement says.
Who benefits most from this drug?
Lecanemab is a treatment for people with early-stage Alzheimer’s disease who have amyloid in their brain. This means people with other types of dementia, or those in the later stages of Alzheimer’s disease, are not likely to improve with this drug.
Who makes lecanemab?
Japan-based Eisai is developing the drug, a monoclonal antibody, in collaboration with the U.S. company Biogen.
What’s the Alzheimer’s Association’s view?
The association urged accelerated FDA approval. In a statement, it says it “welcomes and is further encouraged” by the clinical trial results.
It says data published in the New England Journal of Medicine confirms lecanemab “can meaningfully change the course of the disease for people in the earliest stages of Alzheimer’s disease.”
“We are energized at the progress we are seeing in the research pipeline. The science is telling us that although antiamyloid treatments are not a cure – they are not going to be the end of treating Alzheimer’s – they are certainly the beginning,” Dr. Edelmayer says.
Are there alternatives?
The FDA gave accelerated approval to Biogen to produce another drug for Alzheimer’s, Aduhelm (aducanemab), in 2021, but the move was controversial as the drug’s effectiveness was widely questioned. It has since largely been pulled from the market.
Aduhelm had been the first approved early-stage Alzheimer’s treatment since 2003.
A version of this article first appeared on WebMD.com.
New guidelines on peds obesity call for aggressive treatment
and hope the problem solves itself. That’s the upshot of new guidelines from the American Academy of Pediatrics.
The authors of the guidelines also encourage primary care doctors to collaborate with other medical professionals to treat the comorbidities often linked to obesity, rather than take on the entire challenge themselves.
“It’s impossible to treat obesity within the four walls of the clinic. That’s one thing I have learned,” Ihuoma Eneli, MD, associate director of the AAP Institute for Healthy Childhood Weight, told this news organization. For example, a primary care doctor could partner with a gastroenterologist when treating a child who has nonalcoholic fatty liver disease, added Dr. Eneli, a professor of pediatrics at the Ohio State University, Columbus, who helped write the recommendations.
The new document updates 2007 recommendations from AAP about treating children and adolescents who are overweight or obese. The earlier statement focused on behavioral modification and healthy eating behaviors and paid less attention to weight-lowering medications or bariatric surgery for young people. That document did not offer specific advice to health care providers about how to address childhood overweight or obesity.
The 2023 guidelines recommend that pediatricians offer anyone aged 12 years and older with obesity – defined as a body mass index (BMI) at the 95th percentile or higher – the option of receiving weight-loss medications in addition to ongoing support for lifestyle modifications, such as exercising more and eating healthier foods.
The same approach holds for bariatric surgery once children reach age 13, and AAP stressed that no physician should ever stigmatize children or imply that they are to blame for their weight.
AAP did not receive any industry funding to develop the guidelines.
As children reach the threshold BMI levels, physicians should conduct complete physicals and order blood tests to get a fuller picture of the patients’ health.
These are the first guidelines from AAP aimed at giving pediatricians and other primary care providers concrete guidance for managing overweight and obesity in younger patients.
“Obesity is a complex, chronic disease, and that’s a frame shift here,” said Sandra S. Hassink, MD, leader of the guideline group and director of the AAP Institute for Healthy Childhood Weight.
Dr. Hassink compared obesity to asthma, another chronic disease that merits prompt attention and ongoing treatment. A physician would never let a child with asthma go untreated until their breathing problems are so severe that they turn blue, Dr. Hassink said; similarly, physicians should treat obesity in young people promptly and over time.
While some aspects of treating overweight and obesity are the same for children and adults, Dr. Hassink noted distinct differences. “Every child is embedded in a family and extended support structure,” Dr. Hassink said, which means that any obesity management technique needs the buy-in and support of the child’s family too.
AAP’s new advice reflects current understanding that excess weight or obesity in children is a result of biological and social factors, such as living in a food desert or experiencing the effects of structural racism.
The guidelines synthesize the results of hundreds of studies about the best way to treat excess weight in young people. If multiple studies were of high quality and all reached similar conclusions, they received an “A.” Less robust but still informative studies rated a “B.” In aggregate, the guideline about weight-lowering medication is based on “B” evidence that could shift with further research.
The authors recommend that clinicians calculate a child’s BMI beginning at age 2 years, with particular attention to those at the 85th percentile or higher for their age and sex (which would be defined as overweight), at the 95th percentile or higher (obesity), or at the 120th percentile and higher (severe obesity). Clinicians also should monitor blood pressure and cholesterol in their patients with overweight or obesity, particularly once they reach age 10.
Starting at age 6, providers should interview patients and their families about what would motivate them to lose weight, then tailor interventions to those factors rather than just make a blanket declaration that weight loss is necessary. This step should be coupled with intensive support – ideally, at least 26 hours of face-to-face support over the course of a year, although more is better – about effective exercise and dietary habits that result in weight loss.
The intensive support model should remain in place throughout childhood and adolescence and should be coupled with referrals for weight-loss medications or bariatric surgeries as needed once children reach age 12 or 13. Those age cutoffs are based on current evidence as to when weight-loss medications or surgery becomes effective, Dr. Hassink said, and could be shifted to lower ages if that’s what new evidence shows.
“Intensive health behavioral and lifestyle treatment is the base of all other treatment extensions,” Dr. Eneli said.
Young patients who needed weight-lowering medication used to have fewer options, according to Aaron S. Kelly, PhD, the Minnesota American Legion and Auxiliary Chair in Children’s Health at the University of Minnesota, Minneapolis.
.No longer.
Dr. Kelly was not involved in drafting the guidelines but was the lead investigator for trials of liraglutide (Saxenda), which in 2020 received U.S. Food and Drug Administration approval for treating obesity in adolescents. In 2022, the agency approved phentermine and topiramate extended-release capsules (Qsymia) for long-term weight management for patients aged 12 years and older, along with a once-weekly injection of semaglutide (Wegovy) patients in this age group. There are no weight-lowering medications for children younger than 12, Dr. Kelly said.
“Obesity is not a lifestyle problem. A lot of it is driven by the underlying biology,” Dr. Kelly said. “Really, what these medicines do is make it easier for people to make the right lifestyle choices by pushing back against the biology.”
For example, a drug can make people feel full for longer or disrupt chemical pathways that result in craving certain foods. Dr. Kelly emphasized that these drugs do not give license for people to eat as much as they want.
As for bariatric surgery, the new guidelines adhere closely to those in a 2019 AAP statement that bariatric surgery is safe and effective in pediatric settings. This is gratifying to Kirk W. Reichard, MD, MBA, a lead author of the 2019 article and director of the bariatric surgery program at Nemours Children’s Health.
Even if the information isn’t new as of 2023, Dr. Reichard said, AAP’s imprimatur could cause some eligible families to consider bariatric surgery when they may not have done so before.
Dr. Eneli, Dr. Hassink, and Dr. Reichard reported no relevant financial conflicts of interest. Dr. Kelly has relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Vivus.
A version of this article first appeared on Medscape.com.
and hope the problem solves itself. That’s the upshot of new guidelines from the American Academy of Pediatrics.
The authors of the guidelines also encourage primary care doctors to collaborate with other medical professionals to treat the comorbidities often linked to obesity, rather than take on the entire challenge themselves.
“It’s impossible to treat obesity within the four walls of the clinic. That’s one thing I have learned,” Ihuoma Eneli, MD, associate director of the AAP Institute for Healthy Childhood Weight, told this news organization. For example, a primary care doctor could partner with a gastroenterologist when treating a child who has nonalcoholic fatty liver disease, added Dr. Eneli, a professor of pediatrics at the Ohio State University, Columbus, who helped write the recommendations.
The new document updates 2007 recommendations from AAP about treating children and adolescents who are overweight or obese. The earlier statement focused on behavioral modification and healthy eating behaviors and paid less attention to weight-lowering medications or bariatric surgery for young people. That document did not offer specific advice to health care providers about how to address childhood overweight or obesity.
The 2023 guidelines recommend that pediatricians offer anyone aged 12 years and older with obesity – defined as a body mass index (BMI) at the 95th percentile or higher – the option of receiving weight-loss medications in addition to ongoing support for lifestyle modifications, such as exercising more and eating healthier foods.
The same approach holds for bariatric surgery once children reach age 13, and AAP stressed that no physician should ever stigmatize children or imply that they are to blame for their weight.
AAP did not receive any industry funding to develop the guidelines.
As children reach the threshold BMI levels, physicians should conduct complete physicals and order blood tests to get a fuller picture of the patients’ health.
These are the first guidelines from AAP aimed at giving pediatricians and other primary care providers concrete guidance for managing overweight and obesity in younger patients.
“Obesity is a complex, chronic disease, and that’s a frame shift here,” said Sandra S. Hassink, MD, leader of the guideline group and director of the AAP Institute for Healthy Childhood Weight.
Dr. Hassink compared obesity to asthma, another chronic disease that merits prompt attention and ongoing treatment. A physician would never let a child with asthma go untreated until their breathing problems are so severe that they turn blue, Dr. Hassink said; similarly, physicians should treat obesity in young people promptly and over time.
While some aspects of treating overweight and obesity are the same for children and adults, Dr. Hassink noted distinct differences. “Every child is embedded in a family and extended support structure,” Dr. Hassink said, which means that any obesity management technique needs the buy-in and support of the child’s family too.
AAP’s new advice reflects current understanding that excess weight or obesity in children is a result of biological and social factors, such as living in a food desert or experiencing the effects of structural racism.
The guidelines synthesize the results of hundreds of studies about the best way to treat excess weight in young people. If multiple studies were of high quality and all reached similar conclusions, they received an “A.” Less robust but still informative studies rated a “B.” In aggregate, the guideline about weight-lowering medication is based on “B” evidence that could shift with further research.
The authors recommend that clinicians calculate a child’s BMI beginning at age 2 years, with particular attention to those at the 85th percentile or higher for their age and sex (which would be defined as overweight), at the 95th percentile or higher (obesity), or at the 120th percentile and higher (severe obesity). Clinicians also should monitor blood pressure and cholesterol in their patients with overweight or obesity, particularly once they reach age 10.
Starting at age 6, providers should interview patients and their families about what would motivate them to lose weight, then tailor interventions to those factors rather than just make a blanket declaration that weight loss is necessary. This step should be coupled with intensive support – ideally, at least 26 hours of face-to-face support over the course of a year, although more is better – about effective exercise and dietary habits that result in weight loss.
The intensive support model should remain in place throughout childhood and adolescence and should be coupled with referrals for weight-loss medications or bariatric surgeries as needed once children reach age 12 or 13. Those age cutoffs are based on current evidence as to when weight-loss medications or surgery becomes effective, Dr. Hassink said, and could be shifted to lower ages if that’s what new evidence shows.
“Intensive health behavioral and lifestyle treatment is the base of all other treatment extensions,” Dr. Eneli said.
Young patients who needed weight-lowering medication used to have fewer options, according to Aaron S. Kelly, PhD, the Minnesota American Legion and Auxiliary Chair in Children’s Health at the University of Minnesota, Minneapolis.
.No longer.
Dr. Kelly was not involved in drafting the guidelines but was the lead investigator for trials of liraglutide (Saxenda), which in 2020 received U.S. Food and Drug Administration approval for treating obesity in adolescents. In 2022, the agency approved phentermine and topiramate extended-release capsules (Qsymia) for long-term weight management for patients aged 12 years and older, along with a once-weekly injection of semaglutide (Wegovy) patients in this age group. There are no weight-lowering medications for children younger than 12, Dr. Kelly said.
“Obesity is not a lifestyle problem. A lot of it is driven by the underlying biology,” Dr. Kelly said. “Really, what these medicines do is make it easier for people to make the right lifestyle choices by pushing back against the biology.”
For example, a drug can make people feel full for longer or disrupt chemical pathways that result in craving certain foods. Dr. Kelly emphasized that these drugs do not give license for people to eat as much as they want.
As for bariatric surgery, the new guidelines adhere closely to those in a 2019 AAP statement that bariatric surgery is safe and effective in pediatric settings. This is gratifying to Kirk W. Reichard, MD, MBA, a lead author of the 2019 article and director of the bariatric surgery program at Nemours Children’s Health.
Even if the information isn’t new as of 2023, Dr. Reichard said, AAP’s imprimatur could cause some eligible families to consider bariatric surgery when they may not have done so before.
Dr. Eneli, Dr. Hassink, and Dr. Reichard reported no relevant financial conflicts of interest. Dr. Kelly has relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Vivus.
A version of this article first appeared on Medscape.com.
and hope the problem solves itself. That’s the upshot of new guidelines from the American Academy of Pediatrics.
The authors of the guidelines also encourage primary care doctors to collaborate with other medical professionals to treat the comorbidities often linked to obesity, rather than take on the entire challenge themselves.
“It’s impossible to treat obesity within the four walls of the clinic. That’s one thing I have learned,” Ihuoma Eneli, MD, associate director of the AAP Institute for Healthy Childhood Weight, told this news organization. For example, a primary care doctor could partner with a gastroenterologist when treating a child who has nonalcoholic fatty liver disease, added Dr. Eneli, a professor of pediatrics at the Ohio State University, Columbus, who helped write the recommendations.
The new document updates 2007 recommendations from AAP about treating children and adolescents who are overweight or obese. The earlier statement focused on behavioral modification and healthy eating behaviors and paid less attention to weight-lowering medications or bariatric surgery for young people. That document did not offer specific advice to health care providers about how to address childhood overweight or obesity.
The 2023 guidelines recommend that pediatricians offer anyone aged 12 years and older with obesity – defined as a body mass index (BMI) at the 95th percentile or higher – the option of receiving weight-loss medications in addition to ongoing support for lifestyle modifications, such as exercising more and eating healthier foods.
The same approach holds for bariatric surgery once children reach age 13, and AAP stressed that no physician should ever stigmatize children or imply that they are to blame for their weight.
AAP did not receive any industry funding to develop the guidelines.
As children reach the threshold BMI levels, physicians should conduct complete physicals and order blood tests to get a fuller picture of the patients’ health.
These are the first guidelines from AAP aimed at giving pediatricians and other primary care providers concrete guidance for managing overweight and obesity in younger patients.
“Obesity is a complex, chronic disease, and that’s a frame shift here,” said Sandra S. Hassink, MD, leader of the guideline group and director of the AAP Institute for Healthy Childhood Weight.
Dr. Hassink compared obesity to asthma, another chronic disease that merits prompt attention and ongoing treatment. A physician would never let a child with asthma go untreated until their breathing problems are so severe that they turn blue, Dr. Hassink said; similarly, physicians should treat obesity in young people promptly and over time.
While some aspects of treating overweight and obesity are the same for children and adults, Dr. Hassink noted distinct differences. “Every child is embedded in a family and extended support structure,” Dr. Hassink said, which means that any obesity management technique needs the buy-in and support of the child’s family too.
AAP’s new advice reflects current understanding that excess weight or obesity in children is a result of biological and social factors, such as living in a food desert or experiencing the effects of structural racism.
The guidelines synthesize the results of hundreds of studies about the best way to treat excess weight in young people. If multiple studies were of high quality and all reached similar conclusions, they received an “A.” Less robust but still informative studies rated a “B.” In aggregate, the guideline about weight-lowering medication is based on “B” evidence that could shift with further research.
The authors recommend that clinicians calculate a child’s BMI beginning at age 2 years, with particular attention to those at the 85th percentile or higher for their age and sex (which would be defined as overweight), at the 95th percentile or higher (obesity), or at the 120th percentile and higher (severe obesity). Clinicians also should monitor blood pressure and cholesterol in their patients with overweight or obesity, particularly once they reach age 10.
Starting at age 6, providers should interview patients and their families about what would motivate them to lose weight, then tailor interventions to those factors rather than just make a blanket declaration that weight loss is necessary. This step should be coupled with intensive support – ideally, at least 26 hours of face-to-face support over the course of a year, although more is better – about effective exercise and dietary habits that result in weight loss.
The intensive support model should remain in place throughout childhood and adolescence and should be coupled with referrals for weight-loss medications or bariatric surgeries as needed once children reach age 12 or 13. Those age cutoffs are based on current evidence as to when weight-loss medications or surgery becomes effective, Dr. Hassink said, and could be shifted to lower ages if that’s what new evidence shows.
“Intensive health behavioral and lifestyle treatment is the base of all other treatment extensions,” Dr. Eneli said.
Young patients who needed weight-lowering medication used to have fewer options, according to Aaron S. Kelly, PhD, the Minnesota American Legion and Auxiliary Chair in Children’s Health at the University of Minnesota, Minneapolis.
.No longer.
Dr. Kelly was not involved in drafting the guidelines but was the lead investigator for trials of liraglutide (Saxenda), which in 2020 received U.S. Food and Drug Administration approval for treating obesity in adolescents. In 2022, the agency approved phentermine and topiramate extended-release capsules (Qsymia) for long-term weight management for patients aged 12 years and older, along with a once-weekly injection of semaglutide (Wegovy) patients in this age group. There are no weight-lowering medications for children younger than 12, Dr. Kelly said.
“Obesity is not a lifestyle problem. A lot of it is driven by the underlying biology,” Dr. Kelly said. “Really, what these medicines do is make it easier for people to make the right lifestyle choices by pushing back against the biology.”
For example, a drug can make people feel full for longer or disrupt chemical pathways that result in craving certain foods. Dr. Kelly emphasized that these drugs do not give license for people to eat as much as they want.
As for bariatric surgery, the new guidelines adhere closely to those in a 2019 AAP statement that bariatric surgery is safe and effective in pediatric settings. This is gratifying to Kirk W. Reichard, MD, MBA, a lead author of the 2019 article and director of the bariatric surgery program at Nemours Children’s Health.
Even if the information isn’t new as of 2023, Dr. Reichard said, AAP’s imprimatur could cause some eligible families to consider bariatric surgery when they may not have done so before.
Dr. Eneli, Dr. Hassink, and Dr. Reichard reported no relevant financial conflicts of interest. Dr. Kelly has relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Vivus.
A version of this article first appeared on Medscape.com.
FROM PEDIATRICS
Screen all patients for cannabis use before surgery: Guideline
All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.
One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.
The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
Possible interactions
Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.
“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.
“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.
Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
Risks for vomiting, heart attack
The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.
Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.
The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.
Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.
Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.
The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.
Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.
“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.
For one, it can interact with numerous other drugs, including warfarin.
Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.
Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.
“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.
Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.
A version of this article first appeared on Medscape.com.
All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.
One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.
The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
Possible interactions
Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.
“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.
“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.
Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
Risks for vomiting, heart attack
The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.
Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.
The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.
Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.
Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.
The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.
Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.
“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.
For one, it can interact with numerous other drugs, including warfarin.
Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.
Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.
“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.
Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.
A version of this article first appeared on Medscape.com.
All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.
One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.
The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
Possible interactions
Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.
“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.
“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.
Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
Risks for vomiting, heart attack
The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.
Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.
The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.
Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.
Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.
The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.
Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.
“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.
For one, it can interact with numerous other drugs, including warfarin.
Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.
Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.
“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.
Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.
A version of this article first appeared on Medscape.com.
FROM REGIONAL ANETHESIA AND MEDICINE
Recount of FOURIER data finds higher mortality with evolocumab; trialists push back
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.
The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.
“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”
Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”
Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
Evaluating hard outcomes
The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.
As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.
The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).
Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).
For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.
The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
An ‘obvious disconnect’
Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.
They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.
Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.
At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.
“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.
Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”
Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
The ‘full picture’
Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”
In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.
Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.
When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.
“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.
“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.
Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.
“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”
Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.
Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
Open access
Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.
“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.
“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”
Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”
Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”
The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
Advanced Primary Care program boosts COVID-19 results
The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.
The results were published online in JAMA Network Open.
The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
More vaccinations, more antibody treatments
Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).
Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.
Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
Program components
Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.
The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).
It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.
Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.
As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”
“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
Vaccines and testing made available to providers
Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.
The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.
“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
‘Innovative and important’
Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.
“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”
She said states can learn from each other and this model is an example.
Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.
“But they may be the key components to achieving these outcomes,” she said.
Take-home message
The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.
“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.
Authors report no relevant financial disclosures.
The study received financial support from the Maryland Department of Health.
Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.
The results were published online in JAMA Network Open.
The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
More vaccinations, more antibody treatments
Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).
Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.
Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
Program components
Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.
The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).
It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.
Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.
As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”
“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
Vaccines and testing made available to providers
Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.
The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.
“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
‘Innovative and important’
Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.
“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”
She said states can learn from each other and this model is an example.
Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.
“But they may be the key components to achieving these outcomes,” she said.
Take-home message
The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.
“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.
Authors report no relevant financial disclosures.
The study received financial support from the Maryland Department of Health.
Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.
The results were published online in JAMA Network Open.
The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
More vaccinations, more antibody treatments
Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).
Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.
Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
Program components
Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.
The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).
It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.
Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.
As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”
“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
Vaccines and testing made available to providers
Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.
The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.
“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
‘Innovative and important’
Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.
“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”
She said states can learn from each other and this model is an example.
Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.
“But they may be the key components to achieving these outcomes,” she said.
Take-home message
The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.
“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.
Authors report no relevant financial disclosures.
The study received financial support from the Maryland Department of Health.
Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
FROM JAMA NETWORK OPEN