Sue Hughes

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

The incidence of antidepressant discontinuation symptoms appears to be much lower than was previously thought, results from a new meta-analysis of studies assessing this issue showed.

After accounting for placebo effects, results showed that about 15% of patients who discontinue antidepressant therapy had true discontinuation symptoms, with severe symptoms occurring in about 2% of patients. 

“Considering all available data, we conservatively estimate that one out of every six to seven patients has truly pharmacologically-caused antidepressant discontinuation symptoms. This might still be an over-estimate, as it is difficult to factor in residual or re-emerging symptoms of depression or anxiety,” the researchers concluded. 

The study was published online in The Lancet.
 

More Reliable Data

“We are not saying all antidepressant discontinuation symptoms are a placebo effect. It is a real phenomenon. And we are not saying that there is no problem discontinuing antidepressants. But these findings suggest that true antidepressant discontinuation symptoms are lower than previous studies have suggested,” study investigator, Christopher Baethge, MD, University of Cologne, Germany, said at a Science Media Centre press briefing.

“Our data should de-emotionalize the debate on this issue. Yes, antidepressant discontinuation symptoms are a problem, but they should not cause undue alarm to patients or doctors,” Dr. Baethge added. 

Lead investigator, Jonathan Henssler, MD, Charité – Universitätsmedizin Berlin, Germany, noted that “previous studies on this issue have included surveys which have selection bias in that people with symptoms antidepressant discontinuation are more likely to participate. This study includes a broader range of research and excluded surveys, so we believe these are more reliable results.” 
 

A Controversial Issue

The investigators note that antidepressant discontinuation symptoms can be highly variable and nonspecific, with the most frequently reported symptoms being dizziness, headache, nausea, insomnia, and irritability. These symptoms typically occur within a few days and are usually transient but can last up to several weeks or months.

Explaining the mechanism behind the phenomenon, Dr. Baethge noted that selective serotonin reuptake inhibitor antidepressants increase the available serotonin in the brain, but the body responds by reducing the number of serotonin receptors. If the amount of available serotonin is reduced after stopping the medication, then this can lead to discontinuation symptoms. 

However, the incidence and severity of these symptoms remains controversial, the researchers noted. They point out that some estimates suggest that antidepressant discontinuation symptoms occurred in the majority of patients (56%), with almost half of cases classed as severe. 

Previous attempts at assessment have been questioned on methodologic grounds especially because of inclusion of online surveys or other studies prone to selection and dissatisfaction bias.

“Medical professionals continue to hold polarized positions on the incidence and severity of antidepressant discontinuation symptoms, and the debate continues in public media,” they wrote.

This is the first publication of a larger project on antidepressant discontinuation symptoms.

For the study, the researchers conducted a meta-analysis of 44 controlled trials and 35 observational studies assessing the incidence of antidepressant discontinuation symptoms including a total of 21,002 patients. Of these, 16,532 patients discontinued antidepressant treatment, and 4470 patients discontinued placebo. 

Incidence of at least one antidepressant discontinuation symptom occurred in 31% of patients stopping antidepressant therapy and in 17% after discontinuation of placebo, giving a true rate of pharmacologic-driven antidepressant discontinuation symptoms of 14%-15%.

The study also showed that severe discontinuation symptoms occurred in 2.8% of those stopping antidepressants and in 0.6% of those stopping placebo, giving a true rate of severe antidepressant discontinuation symptoms of around 2%. 

There was no association with treatment duration or with pharmaceutical company funding, and different statistical analyses produced similar results, suggesting the findings are robust, Dr. Baethge reported.

 

Risks by Medication

Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequency of discontinuation symptoms and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms.

Fluoxetine, sertraline, and citalopram had lower rates of discontinuation symptoms. No data were available for bupropion, mirtazapine, and amitriptyline.

As for the clinical implications of the findings, Dr. Henssler said that he does consider discontinuation symptoms when selecting a medication. “I would choose a drug with lower rate of these symptoms unless there was a specific reason to choose one with a higher rate,” he said. 

Dr. Henssler added that these data raise awareness of the placebo effect.

“Considering the placebo results, approximately half of antidepressant discontinuation symptoms could be attributable to expectation or non-specific symptoms,” the researchers noted.

“This is not to say all antidepressant discontinuation symptoms are caused by patient expectations; in practice, all patients discontinuing antidepressants need to be counseled and monitored, and patients who report antidepressant discontinuation symptoms must be helped, in particular those who develop severe antidepressant discontinuation symptoms,” they concluded.

 

Experts Weigh In

Commenting on the study at a press briefing, Oliver Howes, MD, chair of the psychopharmacology committee at the Royal College of Psychiatrists, United Kingdom, said that he welcomed “the insight that this robust study provides.”

“If someone chooses to stop taking their antidepressants, their doctor should help them to do so slowly and in a controlled manner that limits the impact of any potential withdrawal symptoms,” Dr. Howes said.

He added that the Royal College of Psychiatrists has produced a resource for patients and carers on stopping antidepressants that offers information on tapering medication at a pace that suits individual patient needs.

Also commenting, Tony Kendrick, MD, professor of primary care, University of Southampton, United Kingdom, pointed out some limitations of the new meta-analysis — in particular, that the method of assessment of discontinuation symptoms in the included studies was very variable, with specific measurement scales of discontinuation symptoms used in only six of the studies. 

“In most cases the assessment seemed to depend at least partly on the judgment of the authors of the included studies rather than being based on a systematic collection of data,” Dr. Kendrick added.

In an accompanying editorial, Glyn Lewis, PhD, and Gemma Lewis, PhD, University College London, United Kingdom, wrote that though the meta-analysis has its limitations, including the fact that many of the studies were small, often use antidepressants that are not commonly used now, and studied people who had not taken the antidepressants for a very long time, “the results here are a substantial improvement on anything that has been published before.”

They emphasize the importance of discussing the issue of a placebo effect with patients when stopping antidepressants. 

The editorialists pointed out that as antidepressants are prescribed to many millions of people, the relatively uncommon severe withdrawal symptoms will still affect a substantial number of people. However, for individual clinicians, severe withdrawal symptoms will seem uncommon, and most patients will probably not be troubled by antidepressant withdrawal, especially when medication is tapered over a few weeks.

They noted that cessation of antidepressants can lead to an increase in depressive and anxious symptoms, and distinguishing between relapsing symptoms and withdrawal is difficult. 

“Short-term symptoms that reduce quickly, without intervention, are best thought of as a form of withdrawal, even if those symptoms might be similar or identical to the symptoms of depression and anxiety. More serious and longer-term symptoms might best be managed by tapering more slowly, or even deciding to remain on the antidepressant,” the editorialists wrote.

There was no funding source for this study. The authors declare no competing interests. Dr. Kendrick led the NIHR REDUCE trial of internet and telephone support for antidepressant discontinuation and was a member of the guideline committee for the NICE 2022 Depression Guideline.

A version of this article appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

TOPLINE:

Methylphenidate was associated with a small increased risk for cardiovascular events in individuals taking the drug for more than 6 months in a new cohort study.

METHODOLOGY:

• The retrospective, population-based cohort study was based on national Swedish registry data and included 26,710 patients with attention-deficit/hyperactivity disorder (ADHD) aged 12-60 years (median age 20) who had been prescribed methylphenidate between 2007 and 2012. They were each matched on birth date, sex, and county with up to 10 nonusers without ADHD (a total of 225,672 controls).
• Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a Bayesian within-individual design.

TAKEAWAY:

• The overall incidence of cardiovascular events was 1.51 per 10,000 person-weeks for individuals receiving methylphenidate and 0.77 for the matched controls.
• Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41) than matched controls (IRR, 1.18).
• Individuals taking methylphenidate had a 70% posterior probability for a greater than 10% increased risk for cardiovascular events than controls and a 49% posterior probability for an increased risk larger than 20%.
• No difference was found in this risk between individuals with and without a history of cardiovascular disease.

IN PRACTICE:

The researchers concluded that these results support a small (10%) increased risk for cardiovascular events in individuals receiving methylphenidate compared with matched controls after 6 months of treatment. The probability of finding a difference in risk between users and nonusers decreased when considering risk for 20% or larger, with no evidence of differences between those with and without a history of cardiovascular disease. They said the findings suggest the decision to initiate methylphenidate should incorporate considerations of potential adverse cardiovascular effects among the broader benefits and risks for treatment for individual patients.

SOURCE:

The study, led by Miguel Garcia-Argibay, PhD, Örebro University, Örebro, Sweden, was published online in JAMA Network Open on March 6.

LIMITATIONS:

The data were observational, and thus, causality could not be inferred. Lack of information on methylphenidate dose meant that it was not possible to assess a dose effect. Compliance with the medication was also not known, and the association may therefore have been underestimated. The findings of this study were based on data collected from a Swedish population, which may not be representative of other populations.

DISCLOSURES:

The study received funding from the European Union’s Horizon 2020 research and innovation program and the Swedish Research Council for Health, Working Life, and Welfare.

A version of this article appeared on Medscape.com.

TOPLINE:

Methylphenidate was associated with a small increased risk for cardiovascular events in individuals taking the drug for more than 6 months in a new cohort study.

METHODOLOGY:

• The retrospective, population-based cohort study was based on national Swedish registry data and included 26,710 patients with attention-deficit/hyperactivity disorder (ADHD) aged 12-60 years (median age 20) who had been prescribed methylphenidate between 2007 and 2012. They were each matched on birth date, sex, and county with up to 10 nonusers without ADHD (a total of 225,672 controls).
• Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a Bayesian within-individual design.

TAKEAWAY:

• The overall incidence of cardiovascular events was 1.51 per 10,000 person-weeks for individuals receiving methylphenidate and 0.77 for the matched controls.
• Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41) than matched controls (IRR, 1.18).
• Individuals taking methylphenidate had a 70% posterior probability for a greater than 10% increased risk for cardiovascular events than controls and a 49% posterior probability for an increased risk larger than 20%.
• No difference was found in this risk between individuals with and without a history of cardiovascular disease.

IN PRACTICE:

The researchers concluded that these results support a small (10%) increased risk for cardiovascular events in individuals receiving methylphenidate compared with matched controls after 6 months of treatment. The probability of finding a difference in risk between users and nonusers decreased when considering risk for 20% or larger, with no evidence of differences between those with and without a history of cardiovascular disease. They said the findings suggest the decision to initiate methylphenidate should incorporate considerations of potential adverse cardiovascular effects among the broader benefits and risks for treatment for individual patients.

SOURCE:

The study, led by Miguel Garcia-Argibay, PhD, Örebro University, Örebro, Sweden, was published online in JAMA Network Open on March 6.

LIMITATIONS:

The data were observational, and thus, causality could not be inferred. Lack of information on methylphenidate dose meant that it was not possible to assess a dose effect. Compliance with the medication was also not known, and the association may therefore have been underestimated. The findings of this study were based on data collected from a Swedish population, which may not be representative of other populations.

DISCLOSURES:

The study received funding from the European Union’s Horizon 2020 research and innovation program and the Swedish Research Council for Health, Working Life, and Welfare.

A version of this article appeared on Medscape.com.

TOPLINE:

Methylphenidate was associated with a small increased risk for cardiovascular events in individuals taking the drug for more than 6 months in a new cohort study.

METHODOLOGY:

• The retrospective, population-based cohort study was based on national Swedish registry data and included 26,710 patients with attention-deficit/hyperactivity disorder (ADHD) aged 12-60 years (median age 20) who had been prescribed methylphenidate between 2007 and 2012. They were each matched on birth date, sex, and county with up to 10 nonusers without ADHD (a total of 225,672 controls).
• Rates of cardiovascular events, including ischemic heart disease, venous thromboembolism, heart failure, or tachyarrhythmias 1 year before methylphenidate treatment and 6 months after treatment initiation were compared between individuals receiving methylphenidate and matched controls using a Bayesian within-individual design.

TAKEAWAY:

• The overall incidence of cardiovascular events was 1.51 per 10,000 person-weeks for individuals receiving methylphenidate and 0.77 for the matched controls.
• Individuals treated with methylphenidate had an 87% posterior probability of having a higher rate of cardiovascular events after treatment initiation (incidence rate ratio [IRR], 1.41) than matched controls (IRR, 1.18).
• Individuals taking methylphenidate had a 70% posterior probability for a greater than 10% increased risk for cardiovascular events than controls and a 49% posterior probability for an increased risk larger than 20%.
• No difference was found in this risk between individuals with and without a history of cardiovascular disease.

IN PRACTICE:

The researchers concluded that these results support a small (10%) increased risk for cardiovascular events in individuals receiving methylphenidate compared with matched controls after 6 months of treatment. The probability of finding a difference in risk between users and nonusers decreased when considering risk for 20% or larger, with no evidence of differences between those with and without a history of cardiovascular disease. They said the findings suggest the decision to initiate methylphenidate should incorporate considerations of potential adverse cardiovascular effects among the broader benefits and risks for treatment for individual patients.

SOURCE:

The study, led by Miguel Garcia-Argibay, PhD, Örebro University, Örebro, Sweden, was published online in JAMA Network Open on March 6.

LIMITATIONS:

The data were observational, and thus, causality could not be inferred. Lack of information on methylphenidate dose meant that it was not possible to assess a dose effect. Compliance with the medication was also not known, and the association may therefore have been underestimated. The findings of this study were based on data collected from a Swedish population, which may not be representative of other populations.

DISCLOSURES:

The study received funding from the European Union’s Horizon 2020 research and innovation program and the Swedish Research Council for Health, Working Life, and Welfare.

A version of this article appeared on Medscape.com.

Silence Therapeutics shared positive topline 36-week data from its ongoing phase 2 study of zerlasiran, a long-acting agent directed at lowering Lp(a) levels. 

In a statement, the company said the study shows a highly significant reduction from baseline in Lp(a) levels with zerlasiran compared with placebo at 36 weeks, the primary endpoint.

Zerlasiran (formerly known as SLN360), is a short interfering RNA (siRNA) agent, or “ gene silencing” therapy. It binds to and temporarily blocks the action of the LPA gene which encodes for apolipoprotein(a), a dominant and a rate-limiting component in the hepatic synthesis of the Lp(a) particle.

A previous phase 1 study showed that single subcutaneous doses of the drug, ranging from 30 mg to 600 mg, produced a dose-dependent reduction in Lp(a) plasma levels at 45-60 days.

The current double-blind placebo-controlled phase 2 trial — known as ALPACAR-360 — enrolled 178 patients at high risk for atherosclerotic cardiovascular events who had elevated levels of Lp(a), ie, ≥ 125 nmol/L (median baseline Lp(a) was approximately 215 nmol/L). They were randomized to zerlasiran or placebo. 

Zerlasiran was administered at 300 mg subcutaneously every 16 or 24 weeks or at 450 mg every 24 weeks. 

Results reported by the company show a median percentage reduction in Lp(a) of ≥ 90% for both doses at week 36, with no new safety concerns identified during this treatment period.

The 60-week study is ongoing, and secondary endpoints, including change in Lp(a) from baseline to 48 weeks (end of treatment period) and 60 weeks (end of study) and potential effects on other lipids/lipoproteins, will be evaluated.

Silence says it plans to report topline 48-week data from the ALPACAR-360 study in the second quarter of this year.

Elevated levels of Lp(a) represent a genetic risk factor for cardiovascular disease, which is believed to affect approximately 20% of the population. Although there are currently no approved Lp(a)-lowering therapies, several drug candidates are in late-stage clinical testing.

A version of this article appeared on Medscape.com.

Silence Therapeutics shared positive topline 36-week data from its ongoing phase 2 study of zerlasiran, a long-acting agent directed at lowering Lp(a) levels. 

In a statement, the company said the study shows a highly significant reduction from baseline in Lp(a) levels with zerlasiran compared with placebo at 36 weeks, the primary endpoint.

Zerlasiran (formerly known as SLN360), is a short interfering RNA (siRNA) agent, or “ gene silencing” therapy. It binds to and temporarily blocks the action of the LPA gene which encodes for apolipoprotein(a), a dominant and a rate-limiting component in the hepatic synthesis of the Lp(a) particle.

A previous phase 1 study showed that single subcutaneous doses of the drug, ranging from 30 mg to 600 mg, produced a dose-dependent reduction in Lp(a) plasma levels at 45-60 days.

The current double-blind placebo-controlled phase 2 trial — known as ALPACAR-360 — enrolled 178 patients at high risk for atherosclerotic cardiovascular events who had elevated levels of Lp(a), ie, ≥ 125 nmol/L (median baseline Lp(a) was approximately 215 nmol/L). They were randomized to zerlasiran or placebo. 

Zerlasiran was administered at 300 mg subcutaneously every 16 or 24 weeks or at 450 mg every 24 weeks. 

Results reported by the company show a median percentage reduction in Lp(a) of ≥ 90% for both doses at week 36, with no new safety concerns identified during this treatment period.

The 60-week study is ongoing, and secondary endpoints, including change in Lp(a) from baseline to 48 weeks (end of treatment period) and 60 weeks (end of study) and potential effects on other lipids/lipoproteins, will be evaluated.

Silence says it plans to report topline 48-week data from the ALPACAR-360 study in the second quarter of this year.

Elevated levels of Lp(a) represent a genetic risk factor for cardiovascular disease, which is believed to affect approximately 20% of the population. Although there are currently no approved Lp(a)-lowering therapies, several drug candidates are in late-stage clinical testing.

A version of this article appeared on Medscape.com.

Silence Therapeutics shared positive topline 36-week data from its ongoing phase 2 study of zerlasiran, a long-acting agent directed at lowering Lp(a) levels. 

In a statement, the company said the study shows a highly significant reduction from baseline in Lp(a) levels with zerlasiran compared with placebo at 36 weeks, the primary endpoint.

Zerlasiran (formerly known as SLN360), is a short interfering RNA (siRNA) agent, or “ gene silencing” therapy. It binds to and temporarily blocks the action of the LPA gene which encodes for apolipoprotein(a), a dominant and a rate-limiting component in the hepatic synthesis of the Lp(a) particle.

A previous phase 1 study showed that single subcutaneous doses of the drug, ranging from 30 mg to 600 mg, produced a dose-dependent reduction in Lp(a) plasma levels at 45-60 days.

The current double-blind placebo-controlled phase 2 trial — known as ALPACAR-360 — enrolled 178 patients at high risk for atherosclerotic cardiovascular events who had elevated levels of Lp(a), ie, ≥ 125 nmol/L (median baseline Lp(a) was approximately 215 nmol/L). They were randomized to zerlasiran or placebo. 

Zerlasiran was administered at 300 mg subcutaneously every 16 or 24 weeks or at 450 mg every 24 weeks. 

Results reported by the company show a median percentage reduction in Lp(a) of ≥ 90% for both doses at week 36, with no new safety concerns identified during this treatment period.

The 60-week study is ongoing, and secondary endpoints, including change in Lp(a) from baseline to 48 weeks (end of treatment period) and 60 weeks (end of study) and potential effects on other lipids/lipoproteins, will be evaluated.

Silence says it plans to report topline 48-week data from the ALPACAR-360 study in the second quarter of this year.

Elevated levels of Lp(a) represent a genetic risk factor for cardiovascular disease, which is believed to affect approximately 20% of the population. Although there are currently no approved Lp(a)-lowering therapies, several drug candidates are in late-stage clinical testing.

A version of this article appeared on Medscape.com.

The American College of Cardiology has published a new update to its consensus decision pathway for the treatment of heart failure with reduced ejection fraction (HFrEF).

Chair of the consensus document Writing Committee Thomas M. Maddox, MD, explained to this news organization that this new Decision Pathway provides a practical, streamlined update to frontline clinicians treating patients with heart failure and incorporates evidence from the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The authors said that the treatment of heart failure can feel overwhelming, and many opportunities to improve patient outcomes are being missed.

“While the AHA/ACC/HFSA Guidelines are wonderful in that they collate all the latest scientific evidence, they don’t speak as much to the practicalities of delivering the care. This is what this Decision Pathway document comes in — it is designed to help frontline clinicians with the practical reality of managing these patients,” Dr. Maddox, who is director of the Healthcare Innovation Lab at BJC HealthCare and the Washington University School of Medicine in St Louis, Missouri, commented.

The document, “Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction,” was published online on March 8 in the Journal of the American College of Cardiology.

The authors provided guidance on introducing the numerous evidence-based therapies now available for HFrEF, improving adherence, overcoming treatment barriers, acknowledging contraindications and situations for which few data exist, affording expensive therapies, treating special cohorts, and making the transition to palliative care.

Rather than focusing on extensive text, the document provided practical tips, tables, and figures to make clear the steps, tools, and provisos needed to treat patients with heart failure successfully and expeditiously, they added.

Dr. Maddox reported that there are three main updated areas of advice on the treatment of heart failure in the new document.
 

Valsartan/Sacubitril First Line

One of the major changes involves an elevation for the status of the angiotensin receptor-neprilysin inhibitor (ARNI), Entresto (valsartan/sacubitril).

“It is now clear that this agent is superior to ACE-inhibitors or angiotensin receptor blockers in terms of reducing heart failure hospitalization and death, whereas previously it was seen as somewhat equivalent,” Dr. Maddox said. “So, barring a contraindication or another problem with getting the medication, this agent should be one of the first line medicines for all patients with heart failure and a reduced ejection fraction.”
 

Dual Sodium-Glucose Cotransporter 1/2 (SGLT1/2) Inhibitor

A second update involves the addition of sotagliflozin (a dual inhibitor of both SGLT1 and SGLT2) to the SGLT2 inhibitors as another first-line medication for patients with heart failure and reduced ejection fraction.

“We now have evidence that both SGLT2 and SGLT1 inhibitors are beneficial in reducing heart failure hospitalization and death. Previously we only had evidence on SGLT2 inhibitors — dapagliflozin and empagliflozin. Sotagliflozin is a newer agent, which inhibits both SGLT1 and SGLT2, and it turns out that inhibiting both are beneficial in heart failure. So, this gives us a third med in this category,” Dr. Maddox noted.
 

Rapid Initiation of the Four Pillars of Therapy

The document stated that more data have emerged recently to support early and rapid initiation and titration of the “four pillars” of medical therapy in heart failure to maximize the benefits of patient-reported outcomes and reduction in hospitalizations and mortality.

The four pillars of therapy are ARNI, a beta-blocker, a mineralocorticoid antagonist, and an SGLT inhibitor.

As an example, four-class medication initiation reduced the hazard of cardiovascular death or hospital admission for heart failure significantly (hazard ratio, 0.38) compared with therapy with just an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker plus a beta-blocker, the document reported.

“What we realize now is that the more quickly we can get patients on all four of these drug classes and escalate to target doses or maximally tolerated doses ideally within 3 months, the better the outcome,” Dr. Maddox said.

“Unfortunately, right now there is very incomplete realization and recognition of that in clinical practice. So, we are trying to highlight the importance of this to encourage clinicians to be more aggressive in making this happen.”

“In all patients with heart failure and reduced ejection fraction, getting them on all four of these medicines as quickly as possible will give the best outcome. We’ve seen evidence in support of this from several broad population trials,” he added. “There are times when they can’t take all four but we should do our best to get there.”
 

Practical Considerations

Dr. Maddox pointed out that the Consensus Document is also trying to account for practical realities and barriers to heart failure treatment.

“When we think about these recommendations — and evidence that getting patients on all these medicines is valuable, we also focus on the fact that there are three major barriers that can get in the way of this and how to think about overcoming those barriers,” he said.

The barriers are comorbidities/side effects of medications, costs of the medicines, and systems of care that are needed to ensure patients can be treated with multiple medications in a timely fashion.

In terms of comorbidities/side effects, Dr. Maddox explained that patients with heart failure are generally older and are likely to have other comorbidities. “The more medicines we give, the more likely we are to run into side effects. So, we have produced some guidance on how to monitor for adverse effects and ways to mitigate these effects so the guideline recommended therapies can be continued without creating new harms.”

He gave the example of mineralocorticoid antagonists, which can sometimes elevate potassium levels, particularly if there is some underlying kidney disease, so clinicians are advised to recommend a low-potassium diet for these patients or the use of potassium binding agents that will also lower the amount of potassium in the blood stream; in this way, patients are able to continue the mineralocorticoid antagonist.

On costs, Dr. Maddox noted that the valsartan/sacubitril combination drug and SGLT inhibitors are new medicines and are expensive.

“They can be prohibitively expensive for patients who have suboptimal pharmacy benefits or who are uninsured.”

The Consensus Document therefore provided some guidance on ways to identify rebate programs, access insurance, and find different pathways to obtaining those drugs at a more reasonable price. It also advocated for policy changes to allow these medicines to be more accessible to more people.
 

More Use of Digital Tools

On the issue of systems of care, Dr. Maddox noted that the preexisting model of delivering care, which almost always involves the patient coming into the doctor’s office, invokes a high burden on both the system and most especially, the patient.

“Patients do not want to come back and forth to the doctor’s office multiple times in a few weeks. This is often a nonstarter, particularly for patients with busy lives,” he commented.

The Consensus Document advised more use of digital tools to provide remote care and contact with patients including sensors that can measure variables such as heart rate and blood pressure and video appointments.

“We are still working out what are the right models of care and how they can be performed safely and how they can be funded. But I think at the end of the day, this will give us more practical ways of getting people on multiple heart failure medicines and monitoring them safely without causing an undue burden for them logistically,” Dr. Maddox said.

He pointed out that there are a record number of medicines now available to treat heart failure, and while this is welcome, many of these patients are also on multiple other medications for other comorbidities as well.

“If you start giving patients seven, eight, or nine different medicines that they have to take every day, sometimes multiple times a day — that’s complicated medically, logistically, and financially. The potential for interaction and complications increases with every additional medication.”

Dr. Maddox also noted that patients have limits on how many medications they will accept. “It really helps if we have an engaged patient who has a good relationship with the care team to try to develop the right treatment plan that is going to meet their needs and give them the best possible health outcomes.”

It can take many visits to get the patient on all these medications and then up-titrate to target doses.

“We try and do a couple of things in each appointment. Often, we tend to start one or maybe two drugs at a time at a relatively low dose to avoid side effects, so we can be talking about 12-16 different encounters in total,” he said.

He recommended making a plan and the use of new technologies to manage each incremental step.
 

A Team Approach

Another issue that is discussed in the document is the use of a healthcare team to manage all the necessary appointments.

“It is no longer practical that one person can be the engineer for all this. It should be a team effort,” Dr. Maddox stated.

Responsibilities can be allocated across physicians, nurses, pharmacists, and even case managers, so that the team can take more of a population approach and develop a system to get patients on the multiple medications as quickly as possible.

“While this can still be quite a big burden for the patient, we need to figure out a system to make this as palatable as possible for them. Practices need to tailor this themselves according to what resources they have,” he added.

While most new patients will be routed to cardiologists to start their treatment plans, once on their initial medications and these have been up titrated to target levels, they should be able to be managed by primary care doctors, who will have the most holistic view of the patient and their other comorbidities, Dr. Maddox advised.

“Following this guidance should lead to more patients receiving evidence-based care which leads to better health outcomes, but delivered in a practical way that fits with their life reality and logistical needs,” he concluded.

A version of this article appeared on Medscape.com.

The American College of Cardiology has published a new update to its consensus decision pathway for the treatment of heart failure with reduced ejection fraction (HFrEF).

Chair of the consensus document Writing Committee Thomas M. Maddox, MD, explained to this news organization that this new Decision Pathway provides a practical, streamlined update to frontline clinicians treating patients with heart failure and incorporates evidence from the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The authors said that the treatment of heart failure can feel overwhelming, and many opportunities to improve patient outcomes are being missed.

“While the AHA/ACC/HFSA Guidelines are wonderful in that they collate all the latest scientific evidence, they don’t speak as much to the practicalities of delivering the care. This is what this Decision Pathway document comes in — it is designed to help frontline clinicians with the practical reality of managing these patients,” Dr. Maddox, who is director of the Healthcare Innovation Lab at BJC HealthCare and the Washington University School of Medicine in St Louis, Missouri, commented.

The document, “Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction,” was published online on March 8 in the Journal of the American College of Cardiology.

The authors provided guidance on introducing the numerous evidence-based therapies now available for HFrEF, improving adherence, overcoming treatment barriers, acknowledging contraindications and situations for which few data exist, affording expensive therapies, treating special cohorts, and making the transition to palliative care.

Rather than focusing on extensive text, the document provided practical tips, tables, and figures to make clear the steps, tools, and provisos needed to treat patients with heart failure successfully and expeditiously, they added.

Dr. Maddox reported that there are three main updated areas of advice on the treatment of heart failure in the new document.
 

Valsartan/Sacubitril First Line

One of the major changes involves an elevation for the status of the angiotensin receptor-neprilysin inhibitor (ARNI), Entresto (valsartan/sacubitril).

“It is now clear that this agent is superior to ACE-inhibitors or angiotensin receptor blockers in terms of reducing heart failure hospitalization and death, whereas previously it was seen as somewhat equivalent,” Dr. Maddox said. “So, barring a contraindication or another problem with getting the medication, this agent should be one of the first line medicines for all patients with heart failure and a reduced ejection fraction.”
 

Dual Sodium-Glucose Cotransporter 1/2 (SGLT1/2) Inhibitor

A second update involves the addition of sotagliflozin (a dual inhibitor of both SGLT1 and SGLT2) to the SGLT2 inhibitors as another first-line medication for patients with heart failure and reduced ejection fraction.

“We now have evidence that both SGLT2 and SGLT1 inhibitors are beneficial in reducing heart failure hospitalization and death. Previously we only had evidence on SGLT2 inhibitors — dapagliflozin and empagliflozin. Sotagliflozin is a newer agent, which inhibits both SGLT1 and SGLT2, and it turns out that inhibiting both are beneficial in heart failure. So, this gives us a third med in this category,” Dr. Maddox noted.
 

Rapid Initiation of the Four Pillars of Therapy

The document stated that more data have emerged recently to support early and rapid initiation and titration of the “four pillars” of medical therapy in heart failure to maximize the benefits of patient-reported outcomes and reduction in hospitalizations and mortality.

The four pillars of therapy are ARNI, a beta-blocker, a mineralocorticoid antagonist, and an SGLT inhibitor.

As an example, four-class medication initiation reduced the hazard of cardiovascular death or hospital admission for heart failure significantly (hazard ratio, 0.38) compared with therapy with just an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker plus a beta-blocker, the document reported.

“What we realize now is that the more quickly we can get patients on all four of these drug classes and escalate to target doses or maximally tolerated doses ideally within 3 months, the better the outcome,” Dr. Maddox said.

“Unfortunately, right now there is very incomplete realization and recognition of that in clinical practice. So, we are trying to highlight the importance of this to encourage clinicians to be more aggressive in making this happen.”

“In all patients with heart failure and reduced ejection fraction, getting them on all four of these medicines as quickly as possible will give the best outcome. We’ve seen evidence in support of this from several broad population trials,” he added. “There are times when they can’t take all four but we should do our best to get there.”
 

Practical Considerations

Dr. Maddox pointed out that the Consensus Document is also trying to account for practical realities and barriers to heart failure treatment.

“When we think about these recommendations — and evidence that getting patients on all these medicines is valuable, we also focus on the fact that there are three major barriers that can get in the way of this and how to think about overcoming those barriers,” he said.

The barriers are comorbidities/side effects of medications, costs of the medicines, and systems of care that are needed to ensure patients can be treated with multiple medications in a timely fashion.

In terms of comorbidities/side effects, Dr. Maddox explained that patients with heart failure are generally older and are likely to have other comorbidities. “The more medicines we give, the more likely we are to run into side effects. So, we have produced some guidance on how to monitor for adverse effects and ways to mitigate these effects so the guideline recommended therapies can be continued without creating new harms.”

He gave the example of mineralocorticoid antagonists, which can sometimes elevate potassium levels, particularly if there is some underlying kidney disease, so clinicians are advised to recommend a low-potassium diet for these patients or the use of potassium binding agents that will also lower the amount of potassium in the blood stream; in this way, patients are able to continue the mineralocorticoid antagonist.

On costs, Dr. Maddox noted that the valsartan/sacubitril combination drug and SGLT inhibitors are new medicines and are expensive.

“They can be prohibitively expensive for patients who have suboptimal pharmacy benefits or who are uninsured.”

The Consensus Document therefore provided some guidance on ways to identify rebate programs, access insurance, and find different pathways to obtaining those drugs at a more reasonable price. It also advocated for policy changes to allow these medicines to be more accessible to more people.
 

More Use of Digital Tools

On the issue of systems of care, Dr. Maddox noted that the preexisting model of delivering care, which almost always involves the patient coming into the doctor’s office, invokes a high burden on both the system and most especially, the patient.

“Patients do not want to come back and forth to the doctor’s office multiple times in a few weeks. This is often a nonstarter, particularly for patients with busy lives,” he commented.

The Consensus Document advised more use of digital tools to provide remote care and contact with patients including sensors that can measure variables such as heart rate and blood pressure and video appointments.

“We are still working out what are the right models of care and how they can be performed safely and how they can be funded. But I think at the end of the day, this will give us more practical ways of getting people on multiple heart failure medicines and monitoring them safely without causing an undue burden for them logistically,” Dr. Maddox said.

He pointed out that there are a record number of medicines now available to treat heart failure, and while this is welcome, many of these patients are also on multiple other medications for other comorbidities as well.

“If you start giving patients seven, eight, or nine different medicines that they have to take every day, sometimes multiple times a day — that’s complicated medically, logistically, and financially. The potential for interaction and complications increases with every additional medication.”

Dr. Maddox also noted that patients have limits on how many medications they will accept. “It really helps if we have an engaged patient who has a good relationship with the care team to try to develop the right treatment plan that is going to meet their needs and give them the best possible health outcomes.”

It can take many visits to get the patient on all these medications and then up-titrate to target doses.

“We try and do a couple of things in each appointment. Often, we tend to start one or maybe two drugs at a time at a relatively low dose to avoid side effects, so we can be talking about 12-16 different encounters in total,” he said.

He recommended making a plan and the use of new technologies to manage each incremental step.
 

A Team Approach

Another issue that is discussed in the document is the use of a healthcare team to manage all the necessary appointments.

“It is no longer practical that one person can be the engineer for all this. It should be a team effort,” Dr. Maddox stated.

Responsibilities can be allocated across physicians, nurses, pharmacists, and even case managers, so that the team can take more of a population approach and develop a system to get patients on the multiple medications as quickly as possible.

“While this can still be quite a big burden for the patient, we need to figure out a system to make this as palatable as possible for them. Practices need to tailor this themselves according to what resources they have,” he added.

While most new patients will be routed to cardiologists to start their treatment plans, once on their initial medications and these have been up titrated to target levels, they should be able to be managed by primary care doctors, who will have the most holistic view of the patient and their other comorbidities, Dr. Maddox advised.

“Following this guidance should lead to more patients receiving evidence-based care which leads to better health outcomes, but delivered in a practical way that fits with their life reality and logistical needs,” he concluded.

A version of this article appeared on Medscape.com.

The American College of Cardiology has published a new update to its consensus decision pathway for the treatment of heart failure with reduced ejection fraction (HFrEF).

Chair of the consensus document Writing Committee Thomas M. Maddox, MD, explained to this news organization that this new Decision Pathway provides a practical, streamlined update to frontline clinicians treating patients with heart failure and incorporates evidence from the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.

The authors said that the treatment of heart failure can feel overwhelming, and many opportunities to improve patient outcomes are being missed.

“While the AHA/ACC/HFSA Guidelines are wonderful in that they collate all the latest scientific evidence, they don’t speak as much to the practicalities of delivering the care. This is what this Decision Pathway document comes in — it is designed to help frontline clinicians with the practical reality of managing these patients,” Dr. Maddox, who is director of the Healthcare Innovation Lab at BJC HealthCare and the Washington University School of Medicine in St Louis, Missouri, commented.

The document, “Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction,” was published online on March 8 in the Journal of the American College of Cardiology.

The authors provided guidance on introducing the numerous evidence-based therapies now available for HFrEF, improving adherence, overcoming treatment barriers, acknowledging contraindications and situations for which few data exist, affording expensive therapies, treating special cohorts, and making the transition to palliative care.

Rather than focusing on extensive text, the document provided practical tips, tables, and figures to make clear the steps, tools, and provisos needed to treat patients with heart failure successfully and expeditiously, they added.

Dr. Maddox reported that there are three main updated areas of advice on the treatment of heart failure in the new document.
 

Valsartan/Sacubitril First Line

One of the major changes involves an elevation for the status of the angiotensin receptor-neprilysin inhibitor (ARNI), Entresto (valsartan/sacubitril).

“It is now clear that this agent is superior to ACE-inhibitors or angiotensin receptor blockers in terms of reducing heart failure hospitalization and death, whereas previously it was seen as somewhat equivalent,” Dr. Maddox said. “So, barring a contraindication or another problem with getting the medication, this agent should be one of the first line medicines for all patients with heart failure and a reduced ejection fraction.”
 

Dual Sodium-Glucose Cotransporter 1/2 (SGLT1/2) Inhibitor

A second update involves the addition of sotagliflozin (a dual inhibitor of both SGLT1 and SGLT2) to the SGLT2 inhibitors as another first-line medication for patients with heart failure and reduced ejection fraction.

“We now have evidence that both SGLT2 and SGLT1 inhibitors are beneficial in reducing heart failure hospitalization and death. Previously we only had evidence on SGLT2 inhibitors — dapagliflozin and empagliflozin. Sotagliflozin is a newer agent, which inhibits both SGLT1 and SGLT2, and it turns out that inhibiting both are beneficial in heart failure. So, this gives us a third med in this category,” Dr. Maddox noted.
 

Rapid Initiation of the Four Pillars of Therapy

The document stated that more data have emerged recently to support early and rapid initiation and titration of the “four pillars” of medical therapy in heart failure to maximize the benefits of patient-reported outcomes and reduction in hospitalizations and mortality.

The four pillars of therapy are ARNI, a beta-blocker, a mineralocorticoid antagonist, and an SGLT inhibitor.

As an example, four-class medication initiation reduced the hazard of cardiovascular death or hospital admission for heart failure significantly (hazard ratio, 0.38) compared with therapy with just an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker plus a beta-blocker, the document reported.

“What we realize now is that the more quickly we can get patients on all four of these drug classes and escalate to target doses or maximally tolerated doses ideally within 3 months, the better the outcome,” Dr. Maddox said.

“Unfortunately, right now there is very incomplete realization and recognition of that in clinical practice. So, we are trying to highlight the importance of this to encourage clinicians to be more aggressive in making this happen.”

“In all patients with heart failure and reduced ejection fraction, getting them on all four of these medicines as quickly as possible will give the best outcome. We’ve seen evidence in support of this from several broad population trials,” he added. “There are times when they can’t take all four but we should do our best to get there.”
 

Practical Considerations

Dr. Maddox pointed out that the Consensus Document is also trying to account for practical realities and barriers to heart failure treatment.

“When we think about these recommendations — and evidence that getting patients on all these medicines is valuable, we also focus on the fact that there are three major barriers that can get in the way of this and how to think about overcoming those barriers,” he said.

The barriers are comorbidities/side effects of medications, costs of the medicines, and systems of care that are needed to ensure patients can be treated with multiple medications in a timely fashion.

In terms of comorbidities/side effects, Dr. Maddox explained that patients with heart failure are generally older and are likely to have other comorbidities. “The more medicines we give, the more likely we are to run into side effects. So, we have produced some guidance on how to monitor for adverse effects and ways to mitigate these effects so the guideline recommended therapies can be continued without creating new harms.”

He gave the example of mineralocorticoid antagonists, which can sometimes elevate potassium levels, particularly if there is some underlying kidney disease, so clinicians are advised to recommend a low-potassium diet for these patients or the use of potassium binding agents that will also lower the amount of potassium in the blood stream; in this way, patients are able to continue the mineralocorticoid antagonist.

On costs, Dr. Maddox noted that the valsartan/sacubitril combination drug and SGLT inhibitors are new medicines and are expensive.

“They can be prohibitively expensive for patients who have suboptimal pharmacy benefits or who are uninsured.”

The Consensus Document therefore provided some guidance on ways to identify rebate programs, access insurance, and find different pathways to obtaining those drugs at a more reasonable price. It also advocated for policy changes to allow these medicines to be more accessible to more people.
 

More Use of Digital Tools

On the issue of systems of care, Dr. Maddox noted that the preexisting model of delivering care, which almost always involves the patient coming into the doctor’s office, invokes a high burden on both the system and most especially, the patient.

“Patients do not want to come back and forth to the doctor’s office multiple times in a few weeks. This is often a nonstarter, particularly for patients with busy lives,” he commented.

The Consensus Document advised more use of digital tools to provide remote care and contact with patients including sensors that can measure variables such as heart rate and blood pressure and video appointments.

“We are still working out what are the right models of care and how they can be performed safely and how they can be funded. But I think at the end of the day, this will give us more practical ways of getting people on multiple heart failure medicines and monitoring them safely without causing an undue burden for them logistically,” Dr. Maddox said.

He pointed out that there are a record number of medicines now available to treat heart failure, and while this is welcome, many of these patients are also on multiple other medications for other comorbidities as well.

“If you start giving patients seven, eight, or nine different medicines that they have to take every day, sometimes multiple times a day — that’s complicated medically, logistically, and financially. The potential for interaction and complications increases with every additional medication.”

Dr. Maddox also noted that patients have limits on how many medications they will accept. “It really helps if we have an engaged patient who has a good relationship with the care team to try to develop the right treatment plan that is going to meet their needs and give them the best possible health outcomes.”

It can take many visits to get the patient on all these medications and then up-titrate to target doses.

“We try and do a couple of things in each appointment. Often, we tend to start one or maybe two drugs at a time at a relatively low dose to avoid side effects, so we can be talking about 12-16 different encounters in total,” he said.

He recommended making a plan and the use of new technologies to manage each incremental step.
 

A Team Approach

Another issue that is discussed in the document is the use of a healthcare team to manage all the necessary appointments.

“It is no longer practical that one person can be the engineer for all this. It should be a team effort,” Dr. Maddox stated.

Responsibilities can be allocated across physicians, nurses, pharmacists, and even case managers, so that the team can take more of a population approach and develop a system to get patients on the multiple medications as quickly as possible.

“While this can still be quite a big burden for the patient, we need to figure out a system to make this as palatable as possible for them. Practices need to tailor this themselves according to what resources they have,” he added.

While most new patients will be routed to cardiologists to start their treatment plans, once on their initial medications and these have been up titrated to target levels, they should be able to be managed by primary care doctors, who will have the most holistic view of the patient and their other comorbidities, Dr. Maddox advised.

“Following this guidance should lead to more patients receiving evidence-based care which leads to better health outcomes, but delivered in a practical way that fits with their life reality and logistical needs,” he concluded.

A version of this article appeared on Medscape.com.

According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.

This is the first study to show plastic particles are present in atheroma plaques, but the most important finding is that this was related to a four times higher risk for cardiovascular events, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization. 

“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”

The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients. 

After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).

The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.

The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings. 

However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for. 

“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said. 

“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added. 

He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment. 

“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said. 
 

‘Strongly Suggestive of a Causal Relationship’

Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”

“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”

Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”

Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”

He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.” 

Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.” 

He noted that plastics are often already in the food itself, especially seafood. 

“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.” 

Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”

The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.

While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure. 

“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”

He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic. 

“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said. 
 

A version of this article appeared on Medscape.com.

According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.

This is the first study to show plastic particles are present in atheroma plaques, but the most important finding is that this was related to a four times higher risk for cardiovascular events, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization. 

“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”

The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients. 

After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).

The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.

The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings. 

However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for. 

“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said. 

“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added. 

He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment. 

“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said. 
 

‘Strongly Suggestive of a Causal Relationship’

Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”

“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”

Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”

Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”

He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.” 

Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.” 

He noted that plastics are often already in the food itself, especially seafood. 

“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.” 

Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”

The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.

While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure. 

“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”

He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic. 

“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said. 
 

A version of this article appeared on Medscape.com.

According to a new study, patients found to have microplastics and nanoplastics in their carotid artery plaque had a higher risk for death or major cardiovascular events compared with patients who had plaques where particles were not found.

This is the first study to show plastic particles are present in atheroma plaques, but the most important finding is that this was related to a four times higher risk for cardiovascular events, study coauthor Antonio Ceriello, MD, IRCCS MultiMedica, Milan, told this news organization. 

“I believe we have demonstrated that plastics are a new risk factor for cardiovascular disease,” he added. And while plastics may have made our lives easier in many respects, it appears that the price we are paying for that is a shortening of our lives. That is not a good balance.”

The trial involved 304 patients undergoing carotid endarterectomy for asymptomatic carotid artery disease, whose excised plaque specimens were analyzed for the presence of microplastics and nanoplastics, ultimately found in almost 60% of patients. 

After a mean follow-up of 34 months, patients in whom microplastics and nanoplastics were detected within the atheroma had a 4.5 times higher risk for the composite endpoint of all cause death, myocardial infarction, or stroke than those in whom these substances were not detected (hazard ratio, 4.53; 95% CI, 2.00-10.27; P < .001).

The study, led by Raffaele Marfella, MD, University of Campania Luigi Vanvitelli, Naples, Italy, was published in The New England Journal of Medicine on March 7, 2024.

The researchers say the study does not prove causality, and many other unmeasured confounding factors could have contributed to the findings. 

However, Dr. Ceriello noted that many important risk factors such as diabetes, hypertension, and dyslipidemia, were controlled for. 

“In this study, all the patients involved were at high risk of cardiovascular events and they were well treated with statins and antithrombotics, so the relationship between the presence of plastic particles in plaque and cardiovascular events is seen on top of good preventive therapy,” he said. 

“While we cannot say for sure that we have shown a causal relationship, we found a large effect and there is a great deal of literature than supports this. We know that plastic particles can penetrate cells and act at the mitochondrial level to increase free radical production and produce chronic inflammation which is the basis for atherosclerosis,” Dr. Ceriello added. 

He believes there is only one approach to addressing this issue, and that is to reduce the amount of plastic in the environment. 

“Plastic is everywhere — in water pipes, in the ocean. We are hoping that this study will increase the push for government to act on this. This is even more important for the long-term health of our children, who will be exposed to high levels of plastics for the whole of their lives,” he said. 
 

‘Strongly Suggestive of a Causal Relationship’

Commenting for this news organization, Philip J. Landrigan, MD, author of an editorial accompanying publication of the study in the NEJM, described the link as “strongly suggestive.”

“Because this was just a single observational study, it doesn’t prove cause and effect, but I think this is strongly suggestive of a causal relationship,” he said. “While there may be some other confounding factors at play, it is hard for me to imagine that these could account for a hazard ratio of 4.5 — that is a large and alarming increase in just 3 years.”

Dr. Landrigan, who is director of the Program for Global Public Health and the Common Good, Boston College, points out that although it is not known what other exposures may have contributed to the adverse outcomes in patients in this study, the finding of microplastics and nanoplastics in plaque tissue is itself a breakthrough discovery that raises a series of urgent questions. These include: “Should exposure to microplastics and nanoplastics be considered a cardiovascular risk factor? What organs in addition to the heart may be at risk? How can we reduce exposure?”

Dr. Landrigan said he was not surprised that plastic particles had been found in carotid plaques. “Previous studies have found microplastics in other tissues including the lungs, colon and placenta. Now they have turned up in the vessel wall,” he said. “But what is really striking about this study is that it suggests the presence of these plastic particles is causing serious harm.”

He says this should be a wake-up call. “It is telling us that we need to worry about the amount of plastic in our environment. And it is not something that’s going to be a problem down the line — it is affecting us now.” 

Dr. Landrigan explained that plastic particles are taken into the body predominantly by ingestion, which could include drinking from plastic bottles or eating food wrapped in plastic. He said it is particularly damaging to use plastic containers to heat food in the microwave, as heating plastic up drives particles into the food. “That will really increase exposure.” 

He noted that plastics are often already in the food itself, especially seafood. 

“Plastics are dumped in the ocean, they break down and get picked up by the fish. Especially if you eat fish at the top of the food chain like tuna, or if you eat oysters or mussels that are filter feeders, you are more likely to ingest microplastics.” 

Dr. Landrigan said he would not advise against eating fish in general, however. “Maybe tuna or other predatory fish may be an issue, but fish in general are good for us, and fish like salmon which have a mainly vegetarian diet are probably safer in this regard.”

The other route is inhalation, with these small plastic particles being widely present in the air, from sources such as vehicle tires becoming abraded from running along the highway.

While it is impossible to avoid taking in plastic completely, Dr. Landrigan says individuals can make efforts to reduce their exposure. 

“People can make intelligent choices in their homes about what they purchase for themselves and their families, and they can act in their local environments and workplace to try and reduce plastics.”

He noted that 40% of all plastic currently being made is single use plastic, and that percentage is growing, with global production of plastic on track to double by 2040 and triple by 2060, and most of this rapid growth being single use plastic. 

“We are all members of the broader society, and we need to become educated about the plastic situation and lobby our elected officials to come up with a good strong legally binding treaty that will place a cap on plastic production,” Dr. Landrigan said. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

TOPLINE:

Drinking 2 L or more of artificially sweetened drinks per week was associated with a 20% increased risk for atrial fibrillation (AF) in a new observational study.

METHODOLOGY:

• The population-based cohort study looked at the associations of sugar-sweetened beverages, artificial sweetened beverages, and pure fruit juice consumption with the risk for incident AF and evaluated whether genetic susceptibility modifies these associations.
• The authors analyzed data from the UK Biobank on 201,856 participants who were free of baseline AF, had genetic data available, and completed a 24-hour diet questionnaire. The diagnosis of AF was obtained by linkage from primary care, hospital inpatient, and death register records.
• The results were adjusted for a wide range of potential confounders including age, sex, ethnicity, education level, socioeconomic status, smoking, alcohol consumption, physical activity level, sleep duration, body mass index, blood pressure, kidney function, sleep apnea, coronary heart disease, diabetes, and the use of lipid-lowering or antihypertensive medication.

TAKEAWAY:

• During a median follow-up of 9.9 years, 9362 incident AF cases were documented.
• Compared with nonconsumers, individuals who consumed more than 2 L per week of artificially sweetened beverages had a 20% increased risk of developing AF (hazard ratio [HR], 1.20; 95% CI, 1.10-1.31).
• Those who drank more than 2 L per week of sugar-sweetened beverages had a 10% increased risk for AF (HR, 1.10; 95% CI, 1.01-1.20).
• Consumption of 1 L or less per week of pure fruit juice was associated with an 8% lower risk of developing AF (HR, 0.92; 95% CI, 0.87-0.97).
• The associations persisted after adjustment for genetic susceptibility for AF.

IN PRACTICE:

The study authors concluded that this study does not demonstrate that consumption of sugar-sweetened or artificially sweetened beverages alters AF risk but rather that the consumption of these drinks may predict AF risk beyond traditional risk factors. They added that intervention studies and basic research are warranted to confirm whether the observed associations are causal. Commenting on the study, Duane Mellor, MD, registered dietitian at Aston University, Birmingham, England, said it is unclear if the observations in this study are a chance finding as there is a lack of a clear biological link. Naveed Sattar, MD, professor of metabolic medicine at the University of Glasgow, Glasgow, Scotland, added that although the authors tried to adjust for many factors, there is a strong chance that other behavioral aspects linked to beverage choice could be more relevant as a cause of AF rather than the drinks themselves. Tom Sanders, MD, professor emeritus of nutrition and dietetics, King’s College London, London, England, pointed out that as this is the first study that has reported such an effect with artificially sweetened drinks, the finding needs replication before any conclusions can be drawn. “It remains good dietary advice to recommend the consumption of low-calorie artificially sweetened drink in place of sugar-sweetened drinks and alcohol,” he added.

SOURCE:

The study, led by Ying Sun, MD, Shanghai Jiao Tong University School of Medicine, Shanghai, China, was published online in Circulation: Arrhythmia and Electrophysiology.

LIMITATIONS:

The consumption of beverages was self-reported and based on only five separate single-day food intake recalls which were taken over the first 3 years of the study, which was extrapolated to estimate weekly intake. The researchers could not tell whether the sugar-sweetened and artificially sweetened drinks were caffeinated and could not rule out residual confounding by other unmeasured or unknown factors.

DISCLOSURES:

This study was supported by the National Natural Science Foundation of China, Shanghai Municipal Health Commission, Shanghai Municipal Human Resources and Social Security Bureau, Clinical Research Plan of Shanghai Hospital Development Center, Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital, and Shanghai Jiao Tong University School of Medicine.

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Thrombectomy is generally beneficial for patients from a low-income population who have a large vessel occlusion stroke presenting in the later time window and who can be identified as suitable for treatment without the need for advanced and costly imaging, a new Brazilian trial has shown.

“The RESILIENT-Extend trial is the first major study of thrombectomy in the late time window (8-24 h) conducted outside first-world countries and shows the procedure also has benefit in a lower socioeconomic status population without the need for costly imaging equipment,” said lead investigator Raul G. Nogueira, MD. 

“The trial expands the treatment window for thrombectomy globally with simplified selection criteria based on non-contrast CT, potentially altering current guidelines,” Dr. Nogueira said.

However, there were some caveats that need to be considered; in particular, a lack of benefit with thrombectomy in older patients (over 68 years of age), which Dr. Nogueira believes is a reflection of the particular population enrolled in this study. Specifically, he suggested that older age in this low socioeconomic status population is a surrogate for frailty, and the study may have identified frailty as a factor that correlates with reduced or lack of benefit of thrombectomy.

Dr. Nogueira, who is a professor of neurology and neurosurgery at the University of Pittsburgh, and Sheila Martins, MD, a professor of neurology at Hospital de Clinicas Porto Alegre in Brazil, presented the RESILIENT-Extend results at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

Dr. Nogueira explained that the lack of available advanced imaging techniques is a major challenge for implementing endovascular therapy in an extended time window, especially in lower-income countries.

“Our main objective was to see if we could remove the need for advanced imaging to select patients with large vessel occlusion stroke in the late time window (8-24 h) for thrombectomy,” he said. “In this way, our trial overlaps somewhat with the MR CLEAN-LATE Trial conducted in the Netherlands, although the two trials were conducted in very different socioeconomic populations.”

The RESILIENT-Extend trial was conducted in the public health service of Brazil and involved a different population of people than have been included in other thrombectomy trials, which have mostly been conducted in first-world countries.

“The public health system in Brazil is not well-resourced and tends to care for patients at lower socioeconomic levels. These patients are fundamentally different from the average patients in the first-world recruited into most other thrombectomy trials,” Dr. Nogueira noted.

The trial enrolled 245 patients with a large vessel occlusion stroke within 8-24 hours of last known well. Patients were included who had a mismatch between the clinical severity as shown by the National Institutes of Health Stroke Scale (NIHSS) score and the stroke burden on imaging as measured by ASPECTS scores.

They had to have relatively high NIHSS scores (8 or more) showing more severe strokes but also a high ASPECTS score (5-10) excluding patients with large areas of ischemic brain. There was also a sliding scale that adjusted for age to avoid enrolling elderly patients with large strokes.

These patients were identified exclusively using non-contrast CT and CT angiography imaging.

The median age of patients included was 62-63 years. Dr. Nogueira pointed out that patients were slightly younger than seen in other thrombectomy trials, perhaps because in lower-middle-income countries strokes occur at a younger age. They also have a higher case fatality rate.

The median baseline NIHSS score was 16, and the median ASPECTS score was 7-8.

The median time to treatment was 12.5 hours, which is similar to other late window thrombectomy trials.
 

Conflicting Results on Shift Analysis

The primary outcome was a shift analysis of the modified Rankin Scale (mRS) disability score at 90 days.

This showed a bidirectional result, with thrombectomy increasing the chances of a good or excellent outcome (mRS, 0-3), but there was also a nonsignificant increased risk for a bad outcome (mRS, 5-6).

“This bidirectional result prevents a common odds ratio from being calculated, so the primary endpoint is not applicable,” Dr. Nogueira reported.

The researchers therefore used the secondary outcomes as the main results of the study.

These showed that the number of patients achieving a good outcome (mRS, 0-2) was significantly increased with thrombectomy (25% vs. 14%, adjusted odds ratio, 2.56; P = .012).

The number of patients achieving an excellent outcome (mRS, 0-1) was also significantly increased.

But these increases in good outcomes came at the cost of some patients having an increased risk for severe disability or death (mRS, 5-6).

The odds ratio for an mRS of 0-4 versus 5-6 was 0.71, and for an mRS of 0-5 versus 6, the odds ratio was 0.58. Both these results were nonsignificant.

Another anomaly in the RESILIENT-Extend trial was the observation of no benefit of thrombectomy seen in older patients.

“In general, trials of thrombectomy in the first world have shown a greater treatment effect in older patients, but this was not seen in our trial, where older patients (over 68 years) did not derive any benefit from the procedure,” Dr. Nogueira noted.

A similar observation was also seen in the first RESILIENT trial in patients treated within 8 hours of stroke onset, which was also conducted in Brazil, leading to the suggestion that it is related to the patient population included.

“In the Brazilian public health service, older patients are very vulnerable and frail. They are different to older patients in first world countries. It appears they may be too fragile to withstand the thrombectomy process,” Dr. Nogueira said.
 

Frailty: A Ceiling Effect?

Results from the two RESILIENT trials give a word of caution to the thrombectomy field, Dr. Nogueira said.

“This procedure was initially thought suitable only for patients with small core strokes, but we now have a series of trials showing benefit of thrombectomy in large core strokes as well,” Dr. Nogueira said. “We have started to believe that this intervention will benefit almost all patients with large vessel occlusion stroke everywhere around the world, but our data suggest that we have to consider the specific populations that we are serving and that factors such as socioeconomic status and frailty have to be taken into account.

“Both the RESILIENT trials have shown that thrombectomy does not appear to be suitable for older patients, over 68-70 years of age, in the public health service in Brazil,” he noted. “In this population, a patient aged 70 can be quite different to a patient of the same age in a first-world country. I think in our population, an age of over 68-70 is a surrogate for frailty, which will not be the case in first-world countries. In this regard, I think we have found a ceiling effect for benefit of thrombectomy, which is frailty.”

Dr. Nogueira speculated that the bidirectional effect on the mRS shift analysis may also have been caused by the frailty of some of the patients.

“What the results may be showing is that for most of the population, there is a benefit of thrombectomy, but for some patients, possibly the most frail, then the procedure can be too overwhelming for them. But the suggestion of harm was not significant, so this observation could have also just been the play of chance,” he added.
 

Interpreting the Findings

Commenting on the RESILIENT-Extend study results, Michael Hill, MD, professor of neurology at the University of Calgary, Canada, pointed out that there was an absolute benefit of 11.1% on the mRS of 0-2 outcome but a similar signal of harm, with a 10.2% increase in mortality in the thrombectomy group, although that was not statistically significant.

“This signal of harm appears not to be due to an increase in intracranial hemorrhage or procedural mishap,” he said. “It is unclear why there were more deaths; the overall trial numbers are small enough that this could be a chance finding.”

Dr. Hill also noted that the absolute proportion of patients achieving an independent functional outcome was 50% less than in the DAWN trial of thrombectomy in the extended window. “This tells us that the patients selected for inclusion into RESILIENT-Extend were physiologically different from those in DAWN,” he said.

Also commenting on the study, Amrou Sarraj, MD, professor of neurology at University Hospitals Cleveland Medical Center–Case Western Reserve University in Cleveland, said: “The RESILIENT-Extend investigators should be congratulated for the successful conduct of the trial and providing evidence of benefit of thrombectomy procedure with simplified neuroimaging protocol using CT and CTA in resource-limited settings. These findings will help support extending the access to thrombectomy in areas without availability of advanced imaging.”

He said the bidirectional effect on the primary endpoint and the positive interaction between age and thrombectomy treatment effect warranted further investigation.

The RESILIENT-Extend trial was sponsored by the Brazilian Ministry of Health.
 

A version of this article appeared on Medscape.com.

PHOENIX — Black women who develop high blood pressure before age 35 have a threefold increased risk of having a midlife stroke, new observational data suggest. The Black Women’s Health Study, which has followed 59,000 participants in the United States since 1990s, also showed that those who develop hypertension before age 45 have twice the risk of suffering a stroke.

“The really concerning thing about this data is the high proportion of young Black women who had high blood pressure and are suffering strokes relatively early in life,” said the study’s lead author, Hugo J. Aparicio, MD, associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine, Boston. “This can lead to a burden of disability in relatively young women who may be at the prime of their life, pursuing careers, and looking after family.”

Dr. Aparicio presented the data at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

He explained that while there has been good progress in reducing stroke rates in older people over the past decades, there is a concerning observation from multiple datasets showing that stroke rates in midlife have been plateauing or even increasing in recent years.

“For Black women specifically, there is a concern, as we know this group has higher rates of raised blood pressure and stroke overall,” said Dr. Aparicio. “We were interested in looking at whether the onset of hypertension at an earlier age in this group is one of the reasons for the increased stroke risk in midlife.”
 

A Large Study Cohort

The researchers analyzed data from the Black Women’s Health Study; the baseline year for this analysis, which included 46,754 stroke-free participants younger than age 65 (mean age, 42 years), was the 1999 questionnaire.

Both history of hypertension — defined as physician-diagnosed hypertension with the use of an antihypertensive medication — and stroke occurrence were determined by self-report. It has been shown in previous studies that these self-reported data on incidence of hypertension in this dataset are highly reliable, Dr. Aparicio noted.

At baseline, 10.5% of participants aged 45-64 years had hypertension. Stroke occurred in 3.2% of individuals over a mean follow-up of 17 years.

Black women with hypertension before age 45 had a higher risk for midlife stroke (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.79-2.78), after adjustment for age, neighborhood socioeconomic status, residence in the Stroke Belt, smoking, body mass index, and diabetes than women with no history of hypertension.

The risk was also increased with hypertension at midlife ages 45-64 years (HR, 1.69; 95% CI, 1.47-1.95) and was highest among those with hypertension at ages 24-34 years (HR, 3.15; 95% CI, 1.92-5.16).

“Our results show that among young Black women, those with hypertension have a much higher stroke risk than those without hypertension, even if they are taking antihypertensive medication,” Dr. Aparicio said. “This underscores how potent hypertension is as a risk factor for stroke.”

He concluded that both individuals and doctors need to realize that hypertension and stroke are not problems of the elderly exclusively.

“These are conditions that need to be addressed very early in life. This is even more important for Black women, as they are a high-risk group. They need to pay attention to blood pressure numbers early in life — ideally from adolescence — to catch levels before they become too elevated,” Dr. Aparicio said.

“We also need to address lifestyle changes including diet, physical activity, sleep habits, and address other cardiovascular risk factors such as cholesterol and body mass index, so we can prevent strokes from occurring,” he added. “At the policy level, we need to advocate, provide and fund primary prevention measures, and enable earlier screening and better treatment.”
 

The Role of Psychosocial Stressors

Commenting on the study, the American Heart Association immediate past president, Michelle A. Albert, MD, professor of medicine at the University of California, San Francisco, emphasized the importance of regular primary care appointments to screen for high blood pressure and other cardiovascular risk factors.

She pointed out that one of the contributing factors that may increase the risk for Black women is their disproportionate experience of psychosocial stressors and chronic cumulative stress.

This could include stress related to financial issues, racism and other forms of bias, the neighborhood environment, and having to take care of multiple generations of family with limited resources.

“These are some of the things that are less talked about as going into the heightened risk for many cardiovascular risk factors, including hypertension, very early in life for Black women that we need to bring to the forefront of conversations,” Dr. Albert said.

“These stressors not only impact hypertension onset but also they impact one’s ability to be able to seek help, and once the help is sought, to be able to sustain the therapies recommended and the interventions recommended,” she added.

The authors reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

PHOENIX — Black women who develop high blood pressure before age 35 have a threefold increased risk of having a midlife stroke, new observational data suggest. The Black Women’s Health Study, which has followed 59,000 participants in the United States since 1990s, also showed that those who develop hypertension before age 45 have twice the risk of suffering a stroke.

“The really concerning thing about this data is the high proportion of young Black women who had high blood pressure and are suffering strokes relatively early in life,” said the study’s lead author, Hugo J. Aparicio, MD, associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine, Boston. “This can lead to a burden of disability in relatively young women who may be at the prime of their life, pursuing careers, and looking after family.”

Dr. Aparicio presented the data at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

He explained that while there has been good progress in reducing stroke rates in older people over the past decades, there is a concerning observation from multiple datasets showing that stroke rates in midlife have been plateauing or even increasing in recent years.

“For Black women specifically, there is a concern, as we know this group has higher rates of raised blood pressure and stroke overall,” said Dr. Aparicio. “We were interested in looking at whether the onset of hypertension at an earlier age in this group is one of the reasons for the increased stroke risk in midlife.”
 

A Large Study Cohort

The researchers analyzed data from the Black Women’s Health Study; the baseline year for this analysis, which included 46,754 stroke-free participants younger than age 65 (mean age, 42 years), was the 1999 questionnaire.

Both history of hypertension — defined as physician-diagnosed hypertension with the use of an antihypertensive medication — and stroke occurrence were determined by self-report. It has been shown in previous studies that these self-reported data on incidence of hypertension in this dataset are highly reliable, Dr. Aparicio noted.

At baseline, 10.5% of participants aged 45-64 years had hypertension. Stroke occurred in 3.2% of individuals over a mean follow-up of 17 years.

Black women with hypertension before age 45 had a higher risk for midlife stroke (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.79-2.78), after adjustment for age, neighborhood socioeconomic status, residence in the Stroke Belt, smoking, body mass index, and diabetes than women with no history of hypertension.

The risk was also increased with hypertension at midlife ages 45-64 years (HR, 1.69; 95% CI, 1.47-1.95) and was highest among those with hypertension at ages 24-34 years (HR, 3.15; 95% CI, 1.92-5.16).

“Our results show that among young Black women, those with hypertension have a much higher stroke risk than those without hypertension, even if they are taking antihypertensive medication,” Dr. Aparicio said. “This underscores how potent hypertension is as a risk factor for stroke.”

He concluded that both individuals and doctors need to realize that hypertension and stroke are not problems of the elderly exclusively.

“These are conditions that need to be addressed very early in life. This is even more important for Black women, as they are a high-risk group. They need to pay attention to blood pressure numbers early in life — ideally from adolescence — to catch levels before they become too elevated,” Dr. Aparicio said.

“We also need to address lifestyle changes including diet, physical activity, sleep habits, and address other cardiovascular risk factors such as cholesterol and body mass index, so we can prevent strokes from occurring,” he added. “At the policy level, we need to advocate, provide and fund primary prevention measures, and enable earlier screening and better treatment.”
 

The Role of Psychosocial Stressors

Commenting on the study, the American Heart Association immediate past president, Michelle A. Albert, MD, professor of medicine at the University of California, San Francisco, emphasized the importance of regular primary care appointments to screen for high blood pressure and other cardiovascular risk factors.

She pointed out that one of the contributing factors that may increase the risk for Black women is their disproportionate experience of psychosocial stressors and chronic cumulative stress.

This could include stress related to financial issues, racism and other forms of bias, the neighborhood environment, and having to take care of multiple generations of family with limited resources.

“These are some of the things that are less talked about as going into the heightened risk for many cardiovascular risk factors, including hypertension, very early in life for Black women that we need to bring to the forefront of conversations,” Dr. Albert said.

“These stressors not only impact hypertension onset but also they impact one’s ability to be able to seek help, and once the help is sought, to be able to sustain the therapies recommended and the interventions recommended,” she added.

The authors reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

PHOENIX — Black women who develop high blood pressure before age 35 have a threefold increased risk of having a midlife stroke, new observational data suggest. The Black Women’s Health Study, which has followed 59,000 participants in the United States since 1990s, also showed that those who develop hypertension before age 45 have twice the risk of suffering a stroke.

“The really concerning thing about this data is the high proportion of young Black women who had high blood pressure and are suffering strokes relatively early in life,” said the study’s lead author, Hugo J. Aparicio, MD, associate professor of neurology at Boston University Chobanian & Avedisian School of Medicine, Boston. “This can lead to a burden of disability in relatively young women who may be at the prime of their life, pursuing careers, and looking after family.”

Dr. Aparicio presented the data at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

He explained that while there has been good progress in reducing stroke rates in older people over the past decades, there is a concerning observation from multiple datasets showing that stroke rates in midlife have been plateauing or even increasing in recent years.

“For Black women specifically, there is a concern, as we know this group has higher rates of raised blood pressure and stroke overall,” said Dr. Aparicio. “We were interested in looking at whether the onset of hypertension at an earlier age in this group is one of the reasons for the increased stroke risk in midlife.”
 

A Large Study Cohort

The researchers analyzed data from the Black Women’s Health Study; the baseline year for this analysis, which included 46,754 stroke-free participants younger than age 65 (mean age, 42 years), was the 1999 questionnaire.

Both history of hypertension — defined as physician-diagnosed hypertension with the use of an antihypertensive medication — and stroke occurrence were determined by self-report. It has been shown in previous studies that these self-reported data on incidence of hypertension in this dataset are highly reliable, Dr. Aparicio noted.

At baseline, 10.5% of participants aged 45-64 years had hypertension. Stroke occurred in 3.2% of individuals over a mean follow-up of 17 years.

Black women with hypertension before age 45 had a higher risk for midlife stroke (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.79-2.78), after adjustment for age, neighborhood socioeconomic status, residence in the Stroke Belt, smoking, body mass index, and diabetes than women with no history of hypertension.

The risk was also increased with hypertension at midlife ages 45-64 years (HR, 1.69; 95% CI, 1.47-1.95) and was highest among those with hypertension at ages 24-34 years (HR, 3.15; 95% CI, 1.92-5.16).

“Our results show that among young Black women, those with hypertension have a much higher stroke risk than those without hypertension, even if they are taking antihypertensive medication,” Dr. Aparicio said. “This underscores how potent hypertension is as a risk factor for stroke.”

He concluded that both individuals and doctors need to realize that hypertension and stroke are not problems of the elderly exclusively.

“These are conditions that need to be addressed very early in life. This is even more important for Black women, as they are a high-risk group. They need to pay attention to blood pressure numbers early in life — ideally from adolescence — to catch levels before they become too elevated,” Dr. Aparicio said.

“We also need to address lifestyle changes including diet, physical activity, sleep habits, and address other cardiovascular risk factors such as cholesterol and body mass index, so we can prevent strokes from occurring,” he added. “At the policy level, we need to advocate, provide and fund primary prevention measures, and enable earlier screening and better treatment.”
 

The Role of Psychosocial Stressors

Commenting on the study, the American Heart Association immediate past president, Michelle A. Albert, MD, professor of medicine at the University of California, San Francisco, emphasized the importance of regular primary care appointments to screen for high blood pressure and other cardiovascular risk factors.

She pointed out that one of the contributing factors that may increase the risk for Black women is their disproportionate experience of psychosocial stressors and chronic cumulative stress.

This could include stress related to financial issues, racism and other forms of bias, the neighborhood environment, and having to take care of multiple generations of family with limited resources.

“These are some of the things that are less talked about as going into the heightened risk for many cardiovascular risk factors, including hypertension, very early in life for Black women that we need to bring to the forefront of conversations,” Dr. Albert said.

“These stressors not only impact hypertension onset but also they impact one’s ability to be able to seek help, and once the help is sought, to be able to sustain the therapies recommended and the interventions recommended,” she added.

The authors reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.

Intravenous (IV) administration of the antiplatelet agent tirofiban for 72 hours was associated with a reduction in early neurologic deterioration compared with oral aspirin therapy in patients with acute ischemic stroke, in the randomized TREND trial.

The results were presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.

Lead author Zhao Wenbo, MD, Xuanwu Hospital, Beijing, China, noted that neurologic deterioration, characterized by a sudden onset and quick peak of neurologic deficits, is a common phenomenon in acute ischemic stroke and is strongly associated with poor clinical outcomes.

Ischemic stroke progression is the main cause of neurologic deterioration, especially during the first few days after onset, Dr. Wenbo said. Several clinical studies have found that intensive antiplatelet therapy may prevent early neurologic deterioration and improve functional outcomes, but administering oral antiplatelet agents can be difficult because of dysphagia, he reported.

The TREND trial was conducted to investigate whether IV tirofiban could prevent early neurologic deterioration without increasing the risk for symptomatic intracerebral hemorrhage in acute ischemic stroke.

The study included 426 patients with acute ischemic stroke within 24 hours of symptom onset who had a neurologic deficit attributed to focal cerebral ischemia and a National Institutes of Health Stroke Scale (NIHSS) score between 4 and 20 points and who were not treated with thrombolysis or endovascular thrombectomy. Patients with cardioembolic stroke were also excluded.

Patients were a median of 10-12 hours from symptom onset and had a baseline NIHSS score of 5.

They were randomized to IV tirofiban or oral aspirin for 72 hours. All patients were then continued on oral antiplatelet therapy.

The primary efficacy outcome was neurologic deterioration within 72 hours after randomization, defined as an increase in NIHSS score of 4 points or more.

This occurred in nine patients (4.2%) in the tirofiban group vs 28 (13.2%) in the control group (relative risk, 0.32; 95% CI, 0.15-0.66; P = .002).

A consistent benefit of IV tirofiban was seen across all subgroups.

The secondary endpoint of neurologic deterioration within 72 hours after randomization, defined as an increase of NIHSS score of 2 points or more, was also significantly reduced. This occurred in 11.7% of the tirofiban group vs 23.6% of the aspirin group (RR, 0.49; 95% CI, 0.32-0.75; P = .001).

An excellent outcome on the modified Rankin Scale (mRS) disability score (mRS, 0-1) at 90 days was seen in 75% of tirofiban vs 68% of aspirin patients, a nonsignificant difference.

A good outcome (mRS, 0-2) occurred in 89% of tirofiban vs 86% of aspirin patients, again a nonsignificant difference.

There were no symptomatic intracerebral hemorrhages within 72 hours after randomization (the primary safety endpoint) in either group, and the incidence of systemic bleeding also did not differ significantly between the groups.

Dr. Wenbo concluded that further randomized clinical trials are needed to determine the efficacy of tirofiban on functional outcomes.

‘Promising Results’

Commenting on the study for this news organization, conference chair, Tudor Jovin, MD, Cooper Medical School of Rowan University, Camden, New Jersey, and vice-chair, Lauren Sansing, MD, Yale School of Medicine, New Haven, Connecticut, both said they thought the results were promising.

“This study didn’t show any long-term outcome benefit, but this was a smaller study, and the results need to be replicated in a larger study with sufficient power to look at longer-term outcomes,” Sansing noted. “But we don’t have anything better than aspirin at present for these patients, so it’s exciting that there may be something in the pipeline for this group.”

Dr. Jovin pointed out that the TREND trial selected patients on the cause of their stroke, in line with the practice of precision medicine.

“By excluding patients who received thrombolysis or thrombectomy and those who had cardioembolic strokes, we are left with a population who we don’t have many treatment options for,” he said. “These are patients with smaller or moderate strokes who may arrive too late for thrombolysis. It would be great to be able to do something more than just aspirin for these patients.”

Dr. Jovin noted that the study was underpowered to show long-term benefits, but there were some promising trends.

“It stands to reason that if neurologic function does not get worse in the early hours and days after stroke, then the long-term outcomes are likely to be better,” he noted. “But this needs to be confirmed in larger trials.”

Interestingly, another study, the MOST trial, also presented at the ISC-24 meeting, showed no benefit with the IV antithrombotic agents argatroban or eptifibatide on 90-day functional outcomes when added to thrombolysis in acute ischemic stroke.

Dr. Jovin pointed out that the MOST and TREND trials included different populations of patients — the MOST patients received thrombolysis, while the TREND patients did not. And in the MOST trial, about half the patients had a large vessel occlusion and underwent thrombectomy, whereas these patients were excluded in TREND.

Dr. Sansing added that patients in the TREND trial may have had small vessel disease or other atherosclerotic disease, or strokes due to the narrowing of vessels or due to an unknown cause. They were also given 3 days of IV tirofiban, whereas the duration of antithrombotic treatment in MOST was shorter.

The TREND study was funded by the National Key Research and Development Program of China, the National Science Foundation of Beijing Municipality, and the Beijing Municipal Science and Technology Commission.

A version of this article appeared on Medscape.com.