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Jury still out on cardiovascular safety of testosterone
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
FROM THE LANCET HEALTHY LONGEVITY
Data concerns mount despite ISCHEMIA substudy correction
A long-standing request to clarify data irregularities in a 2021 ISCHEMIA substudy resulted in the publication of one correction, with a second correction in the works.
Further, the lone cardiac surgeon on the ISCHEMIA trial steering committee, T. Bruce Ferguson, MD, has resigned from the committee, citing a series of factors, including an inability to reconcile data in the substudy and two additional ISCHEMIA papers currently under review.
As previously reported, cardiac surgeons Faisal Bakaeen, MD, and Joseph Sabik III, MD, notified the journal Circulation in March that the Dr. Reynolds et al. substudy had inconsistencies between data in the main paper and supplemental tables detailing patients’ coronary artery disease (CAD) and ischemia severity.
The substudy found that CAD severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the landmark trial.
Circulation published a correction for the substudy on May 20, explaining that a “formatting error” resulted in data being incorrectly presented in two supplemental tables. It does not mention the surgeons’ letter to the editor, which can be found by clicking the “Q” icon below the paper.
Dr. Bakaeen, from the Cleveland Clinic, and Dr. Sabik, from University Hospitals Cleveland Medical Center, told this news organization that they submitted a second letter to editor on May 23 stating that “significant discrepancies” persist.
For example, 7.2% of participants (179/2,475) had moderate stenosis in one coronary vessel in the corrected Reynolds paper (Supplemental Tables I and II) versus 23.3% (697/2,986) in the primary ISCHEMIA manuscript published in the New England Journal of Medicine (Table S5).
The number of patients with left main ≥ 50% stenosis is, surprisingly, identical in both manuscripts, at 40, they said, despite the denominator dropping from 3,845 participants in the primary study to 2,475 participants with an evaluable modified Duke Prognostic Index score in the substudy.
The number of participants with previous coronary artery bypass surgery (CABG) is also hard to reconcile between manuscripts and, importantly, the substudy doesn’t distinguish between lesions bypassed with patent grafts and unbypassed grafts or those with occluded grafts.
“The fact that the authors are working on a second correction is appreciated, but with such numerous inconsistencies, at some point you reach the conclusion that an independent review of the data is the right thing to do for such a high-profile study that received over $100 million of National Institutes of Health support,” Dr. Bakaeen said. “No one should be satisfied or happy if there is any shadow of doubt here regarding the accuracy of the data.”
Speaking to this news organization prior to the first correction, lead substudy author Harmony Reynolds, MD, NYU Langone Health, detailed in depth how the formatting glitch inadvertently upgraded the number of diseased vessels and lesion severity in two supplemental tables.
She noted, as does the correction, that the data were correctly reported in the main manuscript tables and figures and in the remainder of the supplement.
Dr. Reynolds also said they’re in the process of preparing the data for “public sharing soon,” including the Duke Prognostic score at all levels. Dr. Reynolds had not responded by the time of this publication to a request for further details or a timeline.
The surgeons’ first letter to the editor was rejected because it was submitted outside the journal’s 6-week window for letters and was posted as a public comment April 18 via the research platform, Remarq.
Dr. Bakaeen said they were told their second letter was rejected because of Circulation’s “long standing policy” not to publish letters to the editor regarding manuscript corrections but that a correction is being issued.
Circulation editor-in-chief Joseph A. Hill, MD, PhD, UT Southwestern Medical Center, Dallas, said via email that the journal will update its online policies to more clearly state its requirements for publication and that it has been fully transparent with Dr. Bakaeen and Dr. Sabik regarding where it is in the current process.
He confirmed the surgeons were told June 1 that “after additional review, the authors have determined that whereas there are no errors, an additional minor correction is warranted to clarify the description of the study population and sample size. This correction will be published soon.”
Dr. Hill thanked Dr. Bakaeen and Dr. Sabik for bringing the matter to their attention and said, “It is also important to note that both updates to the Dr. Reynolds et al. paper are published as corrections. However, the results and conclusions of the paper remain unchanged.”
The bigger issue
Importantly, the recent AHA/ACC/SCAI coronary revascularization guidelines used ISCHEMIA data to support downgrading the CABG recommendation from class 1 to class 2B in 3-vessel CAD with normal left ventricular function and from class 1 to 2a in 3-vessel CAD with mild to moderate left ventricular dysfunction.
The trial reported no significant benefit with an initial invasive strategy over medical therapy in stable patients with moderate or severe CAD. European guidelines, however, give CABG a class I recommendation for severe three- or two-vessel disease with proximal left anterior descending (LAD) involvement.
Dr. Sabik and Dr. Bakaeen say patients with severe three- or two-vessel disease with proximal LAD involvement were underrepresented in the randomized trials cited by the guidelines but are the typical CABG patients in modern-day practice.
“That is why it is important to determine the severity of CAD accurately and definitively in ISCHEMIA,” Dr. Bakaeen said. “But the more we look at the data, the more errors we encounter.”
Two U.S. surgical groups that were part of the writing process withdrew support for the revascularization guidelines, as did several international surgical societies, citing the data used to support the changes as well as the makeup of the writing committee.
Dr. Ferguson, now with the medical device manufacturer Perfusio, said he resigned from the ISCHEMIA steering committee on May 8 after being unable to accurately reconcile the ISCHEMIA surgical subset data with the Reynolds substudy and two other ISCHEMIA papers on the CABG subset. At least one of those papers, he noted, was being hurriedly pushed through the review process to counter concerns raised by surgeons regarding interpretation of ISCHEMIA.
“This is the first time in my lengthy career in medicine where a level of political agendaism was actually driving the truck,” he said. “It was appalling to me, and I would have said that if I was an interventional cardiologist looking at the results.”
ISCHEMIA results have also been touted as representing state-of-the-art care around the world, but that didn’t appear to be the case for the surgical subset where, for example, China and India performed most CABGs off pump, and globally there was considerable variation in how surgeons approached surgical revascularization strategies, Dr. Ferguson said. “Whether this variability might impact the guideline discussion and these papers coming out remains to be determined.”
He noted that the study protocol allowed for the ISCHEMIA investigators to evaluate whether the variability in the surgical subset influenced the results by comparing the data to that in the Society of Thoracic Surgeons registry, but this option was never acted upon despite being brought to their attention.
“Something political between 2020 and 2022 has crept into the ISCHEMIA trial mindset gestalt, and I don’t like it,” Dr. Ferguson said. “And this can have enormous consequences.”
Asked whether their letters to Circulation are being used to undermine confidence in the ISCHEMIA findings, Dr. Sabik replied, “It is not about undermining ISCHEMIA, but understanding how applicable ISCHEMIA is to patients having CABG today. Understanding the severity of the CAD in patients enrolled in ISCHEMIA is, therefore, necessary.”
“The authors and Circulation have admitted to errors,” he said. “We want to be sure we understand how severe the errors are.”
“This is just about accuracy in a manuscript that may affect patient treatment and therefore patient lives. We want to make sure it is correct,” Dr. Sabik added.
A version of this article first appeared on Medscape.com.
A long-standing request to clarify data irregularities in a 2021 ISCHEMIA substudy resulted in the publication of one correction, with a second correction in the works.
Further, the lone cardiac surgeon on the ISCHEMIA trial steering committee, T. Bruce Ferguson, MD, has resigned from the committee, citing a series of factors, including an inability to reconcile data in the substudy and two additional ISCHEMIA papers currently under review.
As previously reported, cardiac surgeons Faisal Bakaeen, MD, and Joseph Sabik III, MD, notified the journal Circulation in March that the Dr. Reynolds et al. substudy had inconsistencies between data in the main paper and supplemental tables detailing patients’ coronary artery disease (CAD) and ischemia severity.
The substudy found that CAD severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the landmark trial.
Circulation published a correction for the substudy on May 20, explaining that a “formatting error” resulted in data being incorrectly presented in two supplemental tables. It does not mention the surgeons’ letter to the editor, which can be found by clicking the “Q” icon below the paper.
Dr. Bakaeen, from the Cleveland Clinic, and Dr. Sabik, from University Hospitals Cleveland Medical Center, told this news organization that they submitted a second letter to editor on May 23 stating that “significant discrepancies” persist.
For example, 7.2% of participants (179/2,475) had moderate stenosis in one coronary vessel in the corrected Reynolds paper (Supplemental Tables I and II) versus 23.3% (697/2,986) in the primary ISCHEMIA manuscript published in the New England Journal of Medicine (Table S5).
The number of patients with left main ≥ 50% stenosis is, surprisingly, identical in both manuscripts, at 40, they said, despite the denominator dropping from 3,845 participants in the primary study to 2,475 participants with an evaluable modified Duke Prognostic Index score in the substudy.
The number of participants with previous coronary artery bypass surgery (CABG) is also hard to reconcile between manuscripts and, importantly, the substudy doesn’t distinguish between lesions bypassed with patent grafts and unbypassed grafts or those with occluded grafts.
“The fact that the authors are working on a second correction is appreciated, but with such numerous inconsistencies, at some point you reach the conclusion that an independent review of the data is the right thing to do for such a high-profile study that received over $100 million of National Institutes of Health support,” Dr. Bakaeen said. “No one should be satisfied or happy if there is any shadow of doubt here regarding the accuracy of the data.”
Speaking to this news organization prior to the first correction, lead substudy author Harmony Reynolds, MD, NYU Langone Health, detailed in depth how the formatting glitch inadvertently upgraded the number of diseased vessels and lesion severity in two supplemental tables.
She noted, as does the correction, that the data were correctly reported in the main manuscript tables and figures and in the remainder of the supplement.
Dr. Reynolds also said they’re in the process of preparing the data for “public sharing soon,” including the Duke Prognostic score at all levels. Dr. Reynolds had not responded by the time of this publication to a request for further details or a timeline.
The surgeons’ first letter to the editor was rejected because it was submitted outside the journal’s 6-week window for letters and was posted as a public comment April 18 via the research platform, Remarq.
Dr. Bakaeen said they were told their second letter was rejected because of Circulation’s “long standing policy” not to publish letters to the editor regarding manuscript corrections but that a correction is being issued.
Circulation editor-in-chief Joseph A. Hill, MD, PhD, UT Southwestern Medical Center, Dallas, said via email that the journal will update its online policies to more clearly state its requirements for publication and that it has been fully transparent with Dr. Bakaeen and Dr. Sabik regarding where it is in the current process.
He confirmed the surgeons were told June 1 that “after additional review, the authors have determined that whereas there are no errors, an additional minor correction is warranted to clarify the description of the study population and sample size. This correction will be published soon.”
Dr. Hill thanked Dr. Bakaeen and Dr. Sabik for bringing the matter to their attention and said, “It is also important to note that both updates to the Dr. Reynolds et al. paper are published as corrections. However, the results and conclusions of the paper remain unchanged.”
The bigger issue
Importantly, the recent AHA/ACC/SCAI coronary revascularization guidelines used ISCHEMIA data to support downgrading the CABG recommendation from class 1 to class 2B in 3-vessel CAD with normal left ventricular function and from class 1 to 2a in 3-vessel CAD with mild to moderate left ventricular dysfunction.
The trial reported no significant benefit with an initial invasive strategy over medical therapy in stable patients with moderate or severe CAD. European guidelines, however, give CABG a class I recommendation for severe three- or two-vessel disease with proximal left anterior descending (LAD) involvement.
Dr. Sabik and Dr. Bakaeen say patients with severe three- or two-vessel disease with proximal LAD involvement were underrepresented in the randomized trials cited by the guidelines but are the typical CABG patients in modern-day practice.
“That is why it is important to determine the severity of CAD accurately and definitively in ISCHEMIA,” Dr. Bakaeen said. “But the more we look at the data, the more errors we encounter.”
Two U.S. surgical groups that were part of the writing process withdrew support for the revascularization guidelines, as did several international surgical societies, citing the data used to support the changes as well as the makeup of the writing committee.
Dr. Ferguson, now with the medical device manufacturer Perfusio, said he resigned from the ISCHEMIA steering committee on May 8 after being unable to accurately reconcile the ISCHEMIA surgical subset data with the Reynolds substudy and two other ISCHEMIA papers on the CABG subset. At least one of those papers, he noted, was being hurriedly pushed through the review process to counter concerns raised by surgeons regarding interpretation of ISCHEMIA.
“This is the first time in my lengthy career in medicine where a level of political agendaism was actually driving the truck,” he said. “It was appalling to me, and I would have said that if I was an interventional cardiologist looking at the results.”
ISCHEMIA results have also been touted as representing state-of-the-art care around the world, but that didn’t appear to be the case for the surgical subset where, for example, China and India performed most CABGs off pump, and globally there was considerable variation in how surgeons approached surgical revascularization strategies, Dr. Ferguson said. “Whether this variability might impact the guideline discussion and these papers coming out remains to be determined.”
He noted that the study protocol allowed for the ISCHEMIA investigators to evaluate whether the variability in the surgical subset influenced the results by comparing the data to that in the Society of Thoracic Surgeons registry, but this option was never acted upon despite being brought to their attention.
“Something political between 2020 and 2022 has crept into the ISCHEMIA trial mindset gestalt, and I don’t like it,” Dr. Ferguson said. “And this can have enormous consequences.”
Asked whether their letters to Circulation are being used to undermine confidence in the ISCHEMIA findings, Dr. Sabik replied, “It is not about undermining ISCHEMIA, but understanding how applicable ISCHEMIA is to patients having CABG today. Understanding the severity of the CAD in patients enrolled in ISCHEMIA is, therefore, necessary.”
“The authors and Circulation have admitted to errors,” he said. “We want to be sure we understand how severe the errors are.”
“This is just about accuracy in a manuscript that may affect patient treatment and therefore patient lives. We want to make sure it is correct,” Dr. Sabik added.
A version of this article first appeared on Medscape.com.
A long-standing request to clarify data irregularities in a 2021 ISCHEMIA substudy resulted in the publication of one correction, with a second correction in the works.
Further, the lone cardiac surgeon on the ISCHEMIA trial steering committee, T. Bruce Ferguson, MD, has resigned from the committee, citing a series of factors, including an inability to reconcile data in the substudy and two additional ISCHEMIA papers currently under review.
As previously reported, cardiac surgeons Faisal Bakaeen, MD, and Joseph Sabik III, MD, notified the journal Circulation in March that the Dr. Reynolds et al. substudy had inconsistencies between data in the main paper and supplemental tables detailing patients’ coronary artery disease (CAD) and ischemia severity.
The substudy found that CAD severity, classified using the modified Duke Prognostic Index score, predicted 4-year mortality and myocardial infarction in the landmark trial.
Circulation published a correction for the substudy on May 20, explaining that a “formatting error” resulted in data being incorrectly presented in two supplemental tables. It does not mention the surgeons’ letter to the editor, which can be found by clicking the “Q” icon below the paper.
Dr. Bakaeen, from the Cleveland Clinic, and Dr. Sabik, from University Hospitals Cleveland Medical Center, told this news organization that they submitted a second letter to editor on May 23 stating that “significant discrepancies” persist.
For example, 7.2% of participants (179/2,475) had moderate stenosis in one coronary vessel in the corrected Reynolds paper (Supplemental Tables I and II) versus 23.3% (697/2,986) in the primary ISCHEMIA manuscript published in the New England Journal of Medicine (Table S5).
The number of patients with left main ≥ 50% stenosis is, surprisingly, identical in both manuscripts, at 40, they said, despite the denominator dropping from 3,845 participants in the primary study to 2,475 participants with an evaluable modified Duke Prognostic Index score in the substudy.
The number of participants with previous coronary artery bypass surgery (CABG) is also hard to reconcile between manuscripts and, importantly, the substudy doesn’t distinguish between lesions bypassed with patent grafts and unbypassed grafts or those with occluded grafts.
“The fact that the authors are working on a second correction is appreciated, but with such numerous inconsistencies, at some point you reach the conclusion that an independent review of the data is the right thing to do for such a high-profile study that received over $100 million of National Institutes of Health support,” Dr. Bakaeen said. “No one should be satisfied or happy if there is any shadow of doubt here regarding the accuracy of the data.”
Speaking to this news organization prior to the first correction, lead substudy author Harmony Reynolds, MD, NYU Langone Health, detailed in depth how the formatting glitch inadvertently upgraded the number of diseased vessels and lesion severity in two supplemental tables.
She noted, as does the correction, that the data were correctly reported in the main manuscript tables and figures and in the remainder of the supplement.
Dr. Reynolds also said they’re in the process of preparing the data for “public sharing soon,” including the Duke Prognostic score at all levels. Dr. Reynolds had not responded by the time of this publication to a request for further details or a timeline.
The surgeons’ first letter to the editor was rejected because it was submitted outside the journal’s 6-week window for letters and was posted as a public comment April 18 via the research platform, Remarq.
Dr. Bakaeen said they were told their second letter was rejected because of Circulation’s “long standing policy” not to publish letters to the editor regarding manuscript corrections but that a correction is being issued.
Circulation editor-in-chief Joseph A. Hill, MD, PhD, UT Southwestern Medical Center, Dallas, said via email that the journal will update its online policies to more clearly state its requirements for publication and that it has been fully transparent with Dr. Bakaeen and Dr. Sabik regarding where it is in the current process.
He confirmed the surgeons were told June 1 that “after additional review, the authors have determined that whereas there are no errors, an additional minor correction is warranted to clarify the description of the study population and sample size. This correction will be published soon.”
Dr. Hill thanked Dr. Bakaeen and Dr. Sabik for bringing the matter to their attention and said, “It is also important to note that both updates to the Dr. Reynolds et al. paper are published as corrections. However, the results and conclusions of the paper remain unchanged.”
The bigger issue
Importantly, the recent AHA/ACC/SCAI coronary revascularization guidelines used ISCHEMIA data to support downgrading the CABG recommendation from class 1 to class 2B in 3-vessel CAD with normal left ventricular function and from class 1 to 2a in 3-vessel CAD with mild to moderate left ventricular dysfunction.
The trial reported no significant benefit with an initial invasive strategy over medical therapy in stable patients with moderate or severe CAD. European guidelines, however, give CABG a class I recommendation for severe three- or two-vessel disease with proximal left anterior descending (LAD) involvement.
Dr. Sabik and Dr. Bakaeen say patients with severe three- or two-vessel disease with proximal LAD involvement were underrepresented in the randomized trials cited by the guidelines but are the typical CABG patients in modern-day practice.
“That is why it is important to determine the severity of CAD accurately and definitively in ISCHEMIA,” Dr. Bakaeen said. “But the more we look at the data, the more errors we encounter.”
Two U.S. surgical groups that were part of the writing process withdrew support for the revascularization guidelines, as did several international surgical societies, citing the data used to support the changes as well as the makeup of the writing committee.
Dr. Ferguson, now with the medical device manufacturer Perfusio, said he resigned from the ISCHEMIA steering committee on May 8 after being unable to accurately reconcile the ISCHEMIA surgical subset data with the Reynolds substudy and two other ISCHEMIA papers on the CABG subset. At least one of those papers, he noted, was being hurriedly pushed through the review process to counter concerns raised by surgeons regarding interpretation of ISCHEMIA.
“This is the first time in my lengthy career in medicine where a level of political agendaism was actually driving the truck,” he said. “It was appalling to me, and I would have said that if I was an interventional cardiologist looking at the results.”
ISCHEMIA results have also been touted as representing state-of-the-art care around the world, but that didn’t appear to be the case for the surgical subset where, for example, China and India performed most CABGs off pump, and globally there was considerable variation in how surgeons approached surgical revascularization strategies, Dr. Ferguson said. “Whether this variability might impact the guideline discussion and these papers coming out remains to be determined.”
He noted that the study protocol allowed for the ISCHEMIA investigators to evaluate whether the variability in the surgical subset influenced the results by comparing the data to that in the Society of Thoracic Surgeons registry, but this option was never acted upon despite being brought to their attention.
“Something political between 2020 and 2022 has crept into the ISCHEMIA trial mindset gestalt, and I don’t like it,” Dr. Ferguson said. “And this can have enormous consequences.”
Asked whether their letters to Circulation are being used to undermine confidence in the ISCHEMIA findings, Dr. Sabik replied, “It is not about undermining ISCHEMIA, but understanding how applicable ISCHEMIA is to patients having CABG today. Understanding the severity of the CAD in patients enrolled in ISCHEMIA is, therefore, necessary.”
“The authors and Circulation have admitted to errors,” he said. “We want to be sure we understand how severe the errors are.”
“This is just about accuracy in a manuscript that may affect patient treatment and therefore patient lives. We want to make sure it is correct,” Dr. Sabik added.
A version of this article first appeared on Medscape.com.
CTO PCI success rates rising, with blip during COVID-19, registry shows
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
Technical and procedural success rates for chronic total occlusion percutaneous coronary intervention (CTO PCI) have increased steadily over the past 6 years, with rates of in-hospital major adverse cardiac events (MACE) declining to the 2%-or-lower range in that time.
“CTO PCI technical and procedural success rates are high and continue to increase over time,” Spyridon Kostantinis, MD said in presenting updated results from the international PROGRESS-CTO registry at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“The overall success rate increased from 81.6% in 2018 to 88.1% in 2021,” he added. The overall incidence of in-hospital MACE in that time was “an acceptable” 2.1% without significant changes over that period.
The analysis examined clinical, angiographic and procedural outcomes of 10,249 CTO PCIs performed on 10,019 patients from 63 centers in nine countries during 2016-2021. PROGRESS-CTO stands for Prospective Global Registry for the Study of Chronic Total Occlusion Intervention.
The target CTOs were highly complex, he said, with an average J-CTO (multicenter CTO registry in Japan) score of 2.4 ± 1.3 and PROGRESS-CTO score of 1.3 ± 1. The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%) and the circumflex artery (19%).
The registry also tracked how characteristics of the CTO PCI procedures themselves changed over time. “The septal and the epicardial collaterals were the most common collaterals used for retrograde crossing, with a decreasing trend for epicardial collaterals over time,” said Dr. Kostantinis, a research fellow at the Minneapolis Heart Institute.
Septal collateral use varied between 64% and 69% of cases from 2016 to 2021, but the share of epicardial collaterals declined from 35% to 22% in that time.
“Over time, the range of antegrade wiring as the final successfully crossing strategy increased from 46% in 2016 to 61% in 2021, with a decrease in antegrade dissection and re-entry (ADR) and no change in the retrograde approach,” Dr. Kostantinis said. The percentage of procedures using ADR as the final crossing strategy declined from 18% in 2016 to 12% in 2021, with the rate of retrograde crossings peaking at 21% in 2016 but leveling off to 18% or 19% in the subsequent years.
“An increasing use in the efficiency of antegrade wiring may reflect an improvement in guidewire retrograde crossing as well as the increasing operator expertise,” Dr. Kostantinis said.
The study also found that contrast volume, air kerma radiation dose, fluoroscopy time, and procedure time declined steadily over time. “The potential explanations for these are using new x-ray systems as well as the use of intravascular imaging,” Dr. Kostantinis said.
In 2020, the rates of technical and procedural success, as well as the number of overall procedures, declined from 2019, while MACE rates ticked upward that year, probably because of the COVID-19 pandemic, Dr. Kostantinis said.
“It is true that we noticed a rise in MACE rate from 1.6% in 2019 to 2.7% in 2020, but in 2021 that decreased again to 1.7%,” he said in an interview. “Another potential explanation is the higher angiographic complexity of CTOs treated during that year (2020) that resulted in more adverse events.”
Previous results from the PROGRESS-CTO registry reported the difference in MACE between 2019 and 2020 was significant (P = .01). “So, yes, the difference between those 2 years is significant,” Dr. Kostantinis said. However, he noted, the overall trend was not significant, with a P value of .194.
The risk profile of CTO PCI has improved “slowly” over time, said Kirk N. Garratt, MD, but “it’s not yet were it needs to be.”
He added, “Undoubtedly we’ve learned that, without any question, one method for minimizing the risk is to concentrate these cases in the hands of those that do many of them.” As the number of procedures fell – an “embedded” pandemic impact –“I worry that it’s inevitable that complication rates will tick up a bit,” said Dr. Garratt, director of the Center for Heart and Vascular Health at Christiana Care in Newark, Del.
By the same token, he added, this situation with regard to CTOs “parallels what’s happening elsewhere in interventional medicine and medicine broadly; numbers are increasing and we’re busy again. In most domains we’re not as busy as we had been prepandemic, and time will allow us to catch up.”
PROGRESS-CTO has received funding from the Joseph F. and Mary M. Fleischhacker Foundation and the Abbott Northwestern Hospital Foundation Innovation Grant.
Dr. Kostantinis has no disclosures. Dr. Garratt is an advisory board member for Abbott.
FROM SCAI 2022
Omega-3 supplement sweet spot found for BP reduction
A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.
The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.
“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.
Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.
When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.
Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.
However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.
High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.
In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”
“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.
The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”
They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”
The investigators and editorialists have no disclosures.
A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.
The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.
“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.
Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.
When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.
Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.
However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.
High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.
In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”
“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.
The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”
They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”
The investigators and editorialists have no disclosures.
A meta-analysis of 71 randomized controlled trials has found the sweet spot for omega-3 fatty acid intake for lowering blood pressure: between 2 and 3 g/day. The investigators also reported that people at higher risk for cardiovascular disease may benefit from higher daily intake of omega-3.
The study analyzed data from randomized controlled trials involving 4,973 individuals and published from 1987 to 2020. Most of the trials used a combined supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Outcomes analysis involved the impact of combined DHA-EPA at 1, 2, 3, 4, or 5 grams daily on average changes in both systolic and diastolic BP and compared them with the placebo or control groups who had a combined intake of 0 g/day.
“We found a significant nonlinear dose-response relationship for both SBP and DBP models,” wrote senior author Xinzhi Li, MD, PhD, and colleagues. Dr. Li is program director of the school of pharmacy at Macau University of Science and Technology in Taipa, China.
Most of the trials included in the meta-analysis evaluated fish oil supplements, but a number also included EPA and DHA omega-3 fatty acids consumed in food.
When the investigators analyzed studies that used an average baseline SBP of greater than 130 mm Hg, they found that increasing omega-3 supplementation resulted in strong reductions in SBP and DBP, but not so with people with baseline SBP below 130 mm Hg.
Across the entire cohort, average SBP and DBP changes averaged –2.61 (95% confidence interval, –3.57 to –1.65) and –1.64 (95% CI, –2.29 to –0.99) mm Hg for people taking 2 g/d omega-3 supplements, and –2.61 (95% CI, –3.52 to –1.69) and –1.80 (95% CI, –2.38 to –1.23) for those on 3 g/d. The changes weren’t as robust in higher and lower intake groups overall.
However, the higher the BP, the more robust the reductions. For those with SBP greater than 130 mm Hg, 3 g/d resulted in an average change of –3.22 mm Hg (95% CI, –5.21 to –1.23). In the greater than 80 mm Hg DBP group, 3 g/d of omega-3 resulted in an average –3.81 mm Hg reduction (95% CI, –4.48 to –1.87). In patients with BP greater than 140/90 and hypertension, the reductions were even more pronounced. And in patients with BP greater than 130/80, omega-3 intake of 4-5 g/d had a greater impact than 2-3 g/d, although that benefit didn’t carry over in the greater than 140/90 group.
High cholesterol was also a factor in determining the benefits of omega-3 supplementation on BP, as Dr. Li and colleagues wrote that they found “an approximately linear relationship” between hyperlipidemia and SBP, “suggesting that increasing supplementation was associated with greater reductions in SBP.” Likewise, the study found stronger effects on BP in studies with an average patient age greater than 45 years.
In 2019, the Food and Drug Administration issued an update that consuming combined EPA and DHA may lower BP in the general population and reduce the risk of hypertension, but that “the evidence is inconsistent and inconclusive.”
“However, while our study may add a layer of credible evidence, it does not meet the threshold to make an authorized health claim for omega-3 fatty acids in compliance with FDA regulations,” Dr. Li said.
The study addresses shortcomings of previous studies of omega-3 and BP and by identifying the optimal dose, Marc George, MRCP, PhD, of the Institute of Cardiovascular Science, University College, London, and Ajay Gupta, MD, PhD, of the William Harvey Research Institute at Queen Mary University, London, wrote in an accompanying editorial. “More importantly, they have demonstrated a significantly stronger and increased BP-lowering effect in higher cardiovascular risk groups, such as those with hypertension or hyperlipidemia.”
They also noted that the 2.61–mm Hg reduction in SBP the study reported is “likely to be significant” on a population level. “A 2–mm Hg reduction in SBP is estimated to reduce stroke mortality by 10% and deaths from ischemic heart disease by 7%,” they wrote. “Expressed another way, an analysis in the U.S. population using 2010 data estimates that a population-wide reduction in SBP of 2 mm Hg in those aged 45- 64 years would translate to 30,045 fewer cardiovascular events ([coronary heart disease], stroke, and heart failure).”
The investigators and editorialists have no disclosures.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
LDL lowering to specific targets may offset risk from high Lp(a)
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
MILAN – The increased risk for atherosclerotic cardiovascular disease events caused by elevated lipoprotein(a) levels can potentially be precisely offset by lowering LDL cholesterol to specific levels, suggests a novel study that underscores the importance or early intervention.
The results, derived from an analysis of data on Lp(a) and LDL cholesterol levels and associated genetic risk scores in almost 500,000 individuals from the United Kingdom, have been used to develop a series of age-related targets for lowering LDL cholesterol levels to counter the risk associated with lifetime Lp(a) exposure.
Measuring Lp(a) levels can “substantially refine individual estimates of absolute risk of atherosclerotic cardiovascular disease,” said study presenter Brian A. Ference, MD, Centre for Naturally Randomized Trials, University of Cambridge (England).
This can “directly inform treatment decisions about the intensity of LDL lowering or other risk-factor modification needed to overcome the increased risk caused by Lp(a).”
Dr. Ference said this will allow clinicians to personalize the prevention of atherosclerotic cardiovascular disease and identify people “who may benefit from potent Lp(a)-lowering therapies when they become available.”
The research was presented at the European Atherosclerosis Society (EAS) 2022 congress on May 24.
In addition to producing a tabular version of the intensification of LDL-cholesterol reduction needed to overcome the increased cardiovascular risk at different levels of Lp(a), stratified by age, Dr. Ference is working with the EAS to develop an app to further deliver on that personalized prevention.
It will display an individual’s lifetime risk for myocardial infarction or stroke, with and without the inclusion of Lp(a) levels, and determine not only the percentage of increased risk caused by Lp(a), but also the amount by which LDL cholesterol needs to be lowered to overcome that risk.
“The whole rationale for this study was to say, how can we give practical advice on how to use Lp(a) to inform clinical decisions about how to individualize personal risk reduction,” Dr. Ference told this news organization.
“What the app will do is make it very easy for clinicians to, first, understand how much Lp(a) increases risk, but specifically how they can use that information to directly inform their treatment decisions.”
In addition, Dr. Ference said that it will “show patients why it’s important for them” to intensify LDL lowering to overcome their particular level of Lp(a).
Other key takeaways from the results is the importance of intervention as early as possible to minimize the impact of lifetime exposure to increased Lp(a), and that the reduction in LDL cholesterol required to achieve that remains relatively modest.
For Dr. Ference, this means ideally beginning comprehensive health checks at 30 years of age and starting lipid-lowering interventions immediately for those at risk.
“The good thing about LDL and other causes of atherosclerotic cardiovascular disease is it doesn’t really matter how you lower it,” he said, noting that it could be with diet, lifestyle interventions, or medication.
Handy tool
The new app could be a “handy tool to counsel patients,” Florian Kronenberg, MD, Institute of Genetic Epidemiology, Medical University of Innsbruck, Austria, told this news organization.
“We can say, look, you have high Lp(a),” he said. “This is coming from nature, from your genetics, but here we have a point where we can act on your high risk by lowering LDL further. This is important to explain to the patient,” said Dr. Kronenberg, who was not involved in the study.
He emphasized that it is crucial to get across the idea of an individual’s global risk, with not just Lp(a) or cholesterol levels influencing their likelihood of cardiovascular events, but also their age, blood pressure, smoking status, and underlying genetic risk.
Dr. Kronenberg said the current data will be helpful in explaining to clinicians why they should lower LDL-cholesterol levels when a patients had high Lp(a), again centered on the idea of lowering their global risk.
During his presentation, Dr. Ference noted that an increase in Lp(a) levels is associated with a log-linear increase in atherosclerotic cardiovascular disease that is proportional to the absolute, rather than relative, magnitude of Lp(a) increase.
“Unfortunately, unlike other proteins,” he continued, diet and exercise do not affect levels, and there are currently no effective therapies to lower the risks associated with increased Lp(a) concentrations.
“For that reason,” he said, the 2019 ESC/EAS guidelines for the management of dyslipidemias, on which Dr. Ference was a coauthor, “recommend that we intensify life risk-factor modification in persons with elevated risks.”
However, he added, “this guidance is not specific enough to be useful, and that has created a great deal of inertia among clinicians,” with some concluding that they don’t need to measure Lp(a) “because there’s nothing they can do for it.”
Until the development of novel therapies that directly target Lp(a), the authors sought to quantify the amount of LDL lowering needed to “overcome the increased risk caused by Lp(a),” he said.
They studied data on 455,765 individuals from the UK Biobank who did not have a history of cardiovascular events, diabetes, or any cancer before the age of 30. They also had LDL cholesterol levels below 5 mmol/L at the time of enrollment to exclude people with presumed familial hypercholesterolemia.
The researchers used an Lp(a) genetic risk score based on the variants rs10455872 and rs3798220 and an LDL instrumental variable genetic score comprised of 100 variants to randomly categorize individuals with average Lp(a) levels, higher Lp(a) levels, or higher Lp(a) and lower LDL-cholesterol levels.
The data showed that, with elevated absolute levels of measured Lp(a) and with elevated genetic risk scores, there was a progressive increase in the lifetime risk for major coronary events.
When looking at the combination of both increased Lp(a) levels and lower LDL-cholesterol levels, they found that the increase in risk for major coronary events at Lp(a) of 123 nmol/L could be offset by a reduction in LDL-cholesterol levels of 19.5 mg/dL.
For people with an Lp(a) level of 251 nmol/L, the increase in risk for major coronary events was offset by a reduction in LDL-cholesterol levels of 36.1 mg/dL.
Furthermore, the researchers found that the magnitude of intensification of LDL-cholesterol lowering needed to overcome the risk caused by elevated Lp(a) levels varied by age.
For example, in individuals with an Lp(a) level of 220 nmol/L, the reduction in LDL-cholesterol levels needed to offset the risk for major coronary events was calculated to be 0.8 mmol/L if lipid-lowering was started at 30 years of age, rising to 0.9 mmol/L if started at 40 years, 1.2 mmol/L if started at 50 years, and 1.5 mmol/L if started at 60 years.
This, Dr. Ference said, suggests that “diet and lifestyle modification is unlikely to be an effective strategy if started later.”
No funding was declared. Dr. Ference declared relationships with Amgen, Novartis, Merck, Esperion Therapeutics, Pfizer, Regeneron, Sanofi, AstraZeneca, Eli Lilly, Novo Nordisk, The Medicines Company, Mylan, Daiichi Sankyo, Viatris, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, and KrKa Pharmaceuticals. Dr. Kronenberg declared relationships with Amgen, Novartis, and Kaneka.
A version of this article first appeared on Medscape.com.
AT EAS 2022
Hand outcomes similar with distal or proximal radial cardiac cath
The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.
Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.
“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”
In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”
He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”
The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).
To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed –.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.
Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).
Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.
The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.
“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.
“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”
Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.
The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.
Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.
“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”
In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”
He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”
The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).
To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed –.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.
Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).
Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.
The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.
“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.
“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”
Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.
The first randomized controlled study comparing the use of the emerging distal radial artery access to the traditional proximal access for cardiac catheterization has found no significant differences in postprocedure hand function and other secondary outcomes a month afterward, along with similar rates of bleeding and gaining successful RA access at the time of the procedure.
Karim Al-Azizi, MD, reported results of the single-center, Distal vs. Proximal Radial Artery (DIPRA) study at the Society for Cardiovascular Angiography and Interventions annual scientific sessions. DIPRA randomized 300 patients on a 1:1 basis to cardiac catheterization via either the distal or proximal RAs (dRA or pRA). The trial was conducted at the Baylor Scott & White Health The Heart Hospital–Plano in Richardson, Texas, where Dr. Al-Azizi is an interventional cardiologist and structural heart disease specialist.
“Distal radial artery access is a safe strategy for access for cardiovascular patients with a low complication rate,” Dr. Al-Azizi said. “Similarly, the success with distal vs. radial artery access was noted in the study: No significant bleeding or hematomas were noted in the dRA cohort.”
In an interview, Dr. Al-Azizi added, “Our study is the first of its kind and the first to evaluate the true hand function post distal/radial.”
He explained the rationale for the study. “One of the biggest criticisms that came up a few years ago when distal access was being developed and started gaining some momentum is the fact that it is yet unknown what would be the effect on hand function given the proximity to the fingers, proximity to the nerve, and despite that RA occlusion rates were lower.”
The final DIPRA analysis included 254 patients who completed their 30-day follow-up, 128 of whom were randomized to dRA access, 126 to pRA access. Demographics and procedural characteristics were balanced between both arms. The latter included similarities in sheath size used (6-French in 99.3% of both arms) and type of procedure (35.9% in the dRA and 32.9% in pRA arms had percutaneous coronary angioplasty).
To evaluate the primary outcome of hand function in the catheterization hand, the study used a composite of the Quick Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire, hand-grip test, and thumb/forefinger pinch test. The composite score changed –.4 and .1 in the dRA and pRA arms, respectively (P = .07), which didn’t reach statistical significance, Dr. Al-Azizi said.
Outcomes at the time of intervention were similar. Successful RA access failed in six dRA patients, who were converted to pRA, and in two pRA patients. Overall rates for successful RA access were 96.7% in the distal arm and 98% in the proximal arm (P = .72). Bleeding rates were 0% and 1.4% in the respective arms (P = .25).
Dr. Al-Azizi said that he and his coinvestigators are collecting 1-year outcomes data that they will present next year.
The DIPRA findings “provide reassurance that hand function is not compromised regardless of access site,” Sunil V. Rao, MD, moderator of the session where Dr. Al-Azizi reported the results, said in an interview.
“Prior studies indicated no difference in hand function between radial and femoral access, and now these data indicate no difference between distal radial and proximal radial access.” Dr. Rao, the incoming SCAI president, is a professor at Duke University Medical Center in Durham, N.C., and cardiology section chief at Durham Veterans Affairs Medical Center.
“We do need more patient-reported outcomes in percutaneous coronary intervention studies. The DIPRA study is a great example of this,” Dr. Rao added. “The DIPRA study adds to the body of literature indicating that access site choice is an important aspect of the PCI procedure. With meticulous procedural technique, patients can have an excellent outcome from PCI procedures.”
Dr. Al-Azizi disclosed consulting for Edwards Lifesciences and Phillips. Dr. Rao has no disclosures.
FROM SCAI 2022
SGLT2 inhibitors as first-line therapy in type 2 diabetes?
Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.
Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.
The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.
The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.
“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
Just a beginning step, although trial probably wasn’t long enough
However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”
Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”
Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.
In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.
He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.
“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”
The duration of follow-up in the current study is also a limitation, he added.
“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”
Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”
He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.
“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.
First-line SGLT2 inhibitors versus metformin: Most outcomes similar
The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.
From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.
The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.
Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).
However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.
Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.
Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
How does cost factor in?
A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.
Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.
However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.
He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”
Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”
Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”
The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.
Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.
The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.
The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.
“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
Just a beginning step, although trial probably wasn’t long enough
However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”
Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”
Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.
In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.
He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.
“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”
The duration of follow-up in the current study is also a limitation, he added.
“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”
Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”
He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.
“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.
First-line SGLT2 inhibitors versus metformin: Most outcomes similar
The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.
From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.
The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.
Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).
However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.
Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.
Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
How does cost factor in?
A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.
Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.
However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.
He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”
Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”
Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”
The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.
A version of this article first appeared on Medscape.com.
Use of sodium–glucose cotransporter-2 (SGLT-2) inhibitors rather than metformin as first-line treatment for type 2 diabetes appears to cut the risk for heart failure hospitalization but not myocardial infarction, stroke, or all-cause mortality, a new analysis of real-world data suggests.
Safety findings were similar, except for the fact that genital infections were more common with SGLT-2 inhibitors.
The study was conducted using claims data from two large U.S. insurance databases and Medicare. Propensity score matching was used to account for baseline differences.
The study was conducted by HoJin Shin, BPharm, PhD, a postdoctoral research fellow at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues. The findings were published online in Annals of Internal Medicine.
“Those who start SGLT-2 inhibitors as first line show similar risks, compared with metformin in MI, stroke, and all-cause mortality outcomes. Strikingly and consistently, SGLT-2 inhibitors show lower risk for hospitalization for heart failure, which is consistent with the findings from cardiovascular outcomes trials,” Dr. Shin said in an interview.
Just a beginning step, although trial probably wasn’t long enough
However, she added, “I don’t want to overstate anything. ... We aren’t powered enough to investigate who would benefit the most. ... As a pharmacoepidemiologist, I think it’s my duty to provide high-quality evidence so we can actually help physicians and patients make better decisions on their medication. Our current research is just a beginning step.”
Asked to comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, told this news organization, “This study generally confirmed conclusions from published RCTs [randomized clinical trials]. No real surprises, albeit the conclusions may not fully support some of the most enthusiastic claims for SGLT-2 inhibitors with respect to MI, stroke, and cardiovascular death.”
Indeed, Dr. Taylor noted that only two SGLT-2 inhibitors, canagliflozin and empagliflozin, were shown to have a statistically significant association with decreased major adverse cardiovascular events.
In contrast, neither dapagliflozin nor ertugliflozin showed significant benefit regarding those outcomes.
He also pointed out that those four major SLGT-2 inhibitor cardiovascular outcomes trials were placebo-controlled rather than head-to-head trials in which they were compared to an active comparator such as metformin.
“Viewed in this light, it’s probably not surprising that the present study did not demonstrate a robust benefit for SGLT-2 inhibitors to decrease [major adverse CV events].”
The duration of follow-up in the current study is also a limitation, he added.
“The majority of patients were followed for a year or less. This is probably sufficient to assess the impact of some pharmacological mechanisms, for example, the beneficial impact to decrease risk of heart failure by promoting urinary sodium excretion. However, it’s probably insufficient time to observe a beneficial impact on atherosclerosis. For example, there is typically a lag of several years before statins demonstrate efficacy with respect to adverse cardiovascular events.”
Nevertheless, he said, “it provides strong support for benefit with respect to decreasing risk of hospitalization for heart failure.”
He noted that while metformin is currently significantly cheaper than any SGLT-2 inhibitors, once the latter become available as generics, they will be cheaper, and this will likely have a bearing on prescribing decisions.
“Availability of generic SGLT-2 inhibitors offers potential to transform prescribing patterns for type 2 diabetes,” he noted.
First-line SGLT2 inhibitors versus metformin: Most outcomes similar
The study data came from two commercial U.S. health insurance databases, Optum Clinfomatics Data Mart and IBM Marketscan, and from Medicare fee-for-service enrollees.
From April 2013 through March 2020, a total of 9,334 patients began treatment with first-line SGLT-2 inhibitors; 819,973 patients began taking metformin. After 1:2 propensity score matching for confounders, there were 8,613 participants in the SGLT-2 inhibitor group and 17,226 in the group that began treatment with metformin.
The mean follow-up times were 10.7 months for patients taking SGLT-2 inhibitors and 12.2 months for patients taking metformin.
Incidence rates per 1,000 person-years for the composite of hospitalization for MI, hospitalization for ischemic or hemorrhagic stroke, or all-cause mortality (MI/stroke/mortality) were 15.0 versus 16.2 for SLGT-2 inhibitors versus metformin, not a significant difference (hazard ratio, 0.96).
However, for the composite of heart failure hospitalization or all-cause mortality, the rates were 18.3 versus 23.5, a significant difference, with an HR of 0.80. The benefit was seen beginning at about 6 months.
Compared with metformin, SGLT-2 inhibitors showed a significantly lower risk for heart failure hospitalization (HR, 0.78), a numerically (but not significantly) lower risk for MI (HR, 0.70), and similar risks for stroke, mortality, and MI/stroke/HHF/mortality.
Genital infections were significantly more common with SGLT-2 inhibitors (54.1 vs. 23.7 per 1,000 person-years; HR, 2.19). Other safety measures were similar, including acute kidney injury, bone fractures, severe hypoglycemia, diabetic ketoacidosis, and lower-limb amputations.
How does cost factor in?
A sensitivity analysis aimed at examining the possible effect of unmeasured socioeconomic status showed no difference in cardiovascular benefit for first-line SGLT-2 inhibitors and metformin, compared with first-line dipeptidyl peptidase–4 (DPP-4) inhibitors, which cost more than metformin; it is not known what effect DPP-4 inhibitors have on the cardiovascular outcomes of interest.
Cost and insurance coverage factor into the benefit/risk calculation. Metformin is far less costly than any of the SGLT-2 inhibitors – roughly $10 to $20 per month, compared with more than $500 a month.
However, “for some fortunate patients with the most generous pharmacy benefit insurance coverage, the out-of-pocket cost of brand name drugs like SGLT-2 inhibitors is substantially lower,” Dr. Taylor noted.
He said that the current study “raises questions about whether the clinical benefits of SGLT-2 inhibitors as initial monotherapy justify the higher price relative to metformin. The data in this paper suggest that the value case for SGLT-2 inhibitors is strongest for patients with the greatest risk to be hospitalized for heart failure.”
Indeed, Dr. Shin said, “Once we get more information, it may just help in extending the coverage from insurance companies and Medicare/Medicaid, to lower the barrier to access.”
Dr. Taylor reiterated that patents on some of the early SGLT-2 inhibitors are expected to expire in the next few years, which would make it possible for generic versions to be approved. “At that point, prices would likely fall, possibly to levels similar to metformin.”
The study was funded by grant support from the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, and Harvard Medical School, the National Institute on Aging, and the Patient-Centered Outcomes Research Institute. Dr. Shin has disclosed no relevant financial relationships. Dr. Taylor is a consultant for Ionis Pharmaceuticals.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
SAFE-PAD shows long-term safety of paclitaxel devices
Patients who have paclitaxel-coated stents and balloons have survival and outcomes comparable to those who have a bare-metal stent or percutaneous transluminal angioplasty, according to updated results from a large study of almost 170,000 Medicare beneficiaries.
The SAFE-PAD study analyzed Medicare claims data of 168,533 patients, including 70,584 who were treated with drug-coated devices (DCD), from April 2015 through 2018.
Notably, Eric A. Secemsky, MD, MSc, said in an interview, that included more than 32,000 patients with more than 5 years of follow-up. He presented the results at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“What we’re seeing now with this study is that paclitaxel-coated devices [PCDs] have the same long-term survival compared to those treated with non–drug-coated devices (NDCDs),” said Dr. Secemsky, director of vascular intervention at Beth Israel Deaconess Medical Center in Boston. “I think this is another important piece and some of the longest-term data in this size population to demonstrate the long-term safety of PCD, and hopefully it will help us get back to normal practice that has been halted now for over 3 years.”
That was a reference to the 2018 meta-analysis by Konstantinos Katsanos, MD, PhD, of Patras University in Greece, and colleagues, which showed an increased risk of death after PCD placements. That study threw a wet blanket of sorts on PCD use, Dr. Secemsky said.
The median follow-up for SAFE-PAD (formally called the Safety Assessment of Femoropopliteal Endovascular treatment with Paclitaxel-coated Devices) was 3.5 years, with the longest follow-up, 6.3 years. The weighted cumulative incidence of mortality at 6.3 years was 63.6% with NDCDs and 62.5% with DCDs (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99; P < .0001). A subgroup analysis found no link between DCDs and increased death in low-risk patients, low-comorbid patients, inpatient or outpatient treatment, patients without critical limb ischemia, or patients treated with stents or balloon angioplasty alone.
“This report and the length of follow-up is one more piece that has continued to demonstrate safety with PCDs,” Dr. Secemsky said. He added that these results fall in line with smaller studies that failed to show a link between DCDs and long-term mortality, notably the SWEDEPAD randomized study of 2,289 patients evaluated through 4 years, and a subanalysis of 4,000 patients in VOYAGER-PAD through 42 months of follow-up.
“So we’ve really shown through these data sets and others that we can’t replicate any harms that we’ve seen in that Katsanos meta-analysis, and it suggests that there was some bias in that meta-analysis.”
Strengths of the study are its size and the way it followed the patients longitudinally, Sahil A. Parikh, MD, director of endovascular services at Columbia University Vagelos College of Physicians and Surgeons in New York, said in an interview.
With regard to its limitations, Dr. Parikh said, “On the other hand, it’s a claims database which doesn’t have the granularity about the patients’ specific procedural factors,” he said. “There are gaps that might further inform the value of lack thereof of the drug-coated device, but certainly at the topline, which is the hard endpoint of mortality, you can read quite a lot and you can assume that with such large numbers, the signal-to-noise ratio would be sufficiently sensitive that you get a real signal.”
With these updated SAFE-PAD results along with other studies, Dr. Parikh said, “If one weighs the risk benefit of cardiac lesion revascularization regarding requiring a repeat procedure vs. the risk of mortality from paclitaxel, if there is such a thing, I think most physicians have come back and the pendulum has swung back considering it reasonable to use paclitaxel products.”
That’s a message that will resonate with patients reluctant to return to the hospital since the COVID-19 outbreak, he said. “If you can tell them we can avoid a repeat trip to the hospital, they’re all for it,” Dr. Parikh said.
The study results were published simultaneously with Dr. Secemsky’s presentation. Funding for SAFE-PAD came from a multi-industry consortium consisting of BD, Boston Scientific, Cook Medical, Medtronic and Philips, which wasn’t involved in the study design or analysis.
Dr. Secemsky disclosed relationships with Abbott, BD, Bayer, Boston Scientific, Cook Medical, CSI, Endovascular Engineering, Inari, Janssen, Medtronic, Philips, and Venture Med. Dr. Parikh disclosed relationships with TriReme Medical, Boston Scientific, Heartflow, Cordis, Janssen, Terumo, Canon, Shockwave, Abiomed, Abbott, Cardiovascular Systems, Inari and Surmodics.
Patients who have paclitaxel-coated stents and balloons have survival and outcomes comparable to those who have a bare-metal stent or percutaneous transluminal angioplasty, according to updated results from a large study of almost 170,000 Medicare beneficiaries.
The SAFE-PAD study analyzed Medicare claims data of 168,533 patients, including 70,584 who were treated with drug-coated devices (DCD), from April 2015 through 2018.
Notably, Eric A. Secemsky, MD, MSc, said in an interview, that included more than 32,000 patients with more than 5 years of follow-up. He presented the results at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“What we’re seeing now with this study is that paclitaxel-coated devices [PCDs] have the same long-term survival compared to those treated with non–drug-coated devices (NDCDs),” said Dr. Secemsky, director of vascular intervention at Beth Israel Deaconess Medical Center in Boston. “I think this is another important piece and some of the longest-term data in this size population to demonstrate the long-term safety of PCD, and hopefully it will help us get back to normal practice that has been halted now for over 3 years.”
That was a reference to the 2018 meta-analysis by Konstantinos Katsanos, MD, PhD, of Patras University in Greece, and colleagues, which showed an increased risk of death after PCD placements. That study threw a wet blanket of sorts on PCD use, Dr. Secemsky said.
The median follow-up for SAFE-PAD (formally called the Safety Assessment of Femoropopliteal Endovascular treatment with Paclitaxel-coated Devices) was 3.5 years, with the longest follow-up, 6.3 years. The weighted cumulative incidence of mortality at 6.3 years was 63.6% with NDCDs and 62.5% with DCDs (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99; P < .0001). A subgroup analysis found no link between DCDs and increased death in low-risk patients, low-comorbid patients, inpatient or outpatient treatment, patients without critical limb ischemia, or patients treated with stents or balloon angioplasty alone.
“This report and the length of follow-up is one more piece that has continued to demonstrate safety with PCDs,” Dr. Secemsky said. He added that these results fall in line with smaller studies that failed to show a link between DCDs and long-term mortality, notably the SWEDEPAD randomized study of 2,289 patients evaluated through 4 years, and a subanalysis of 4,000 patients in VOYAGER-PAD through 42 months of follow-up.
“So we’ve really shown through these data sets and others that we can’t replicate any harms that we’ve seen in that Katsanos meta-analysis, and it suggests that there was some bias in that meta-analysis.”
Strengths of the study are its size and the way it followed the patients longitudinally, Sahil A. Parikh, MD, director of endovascular services at Columbia University Vagelos College of Physicians and Surgeons in New York, said in an interview.
With regard to its limitations, Dr. Parikh said, “On the other hand, it’s a claims database which doesn’t have the granularity about the patients’ specific procedural factors,” he said. “There are gaps that might further inform the value of lack thereof of the drug-coated device, but certainly at the topline, which is the hard endpoint of mortality, you can read quite a lot and you can assume that with such large numbers, the signal-to-noise ratio would be sufficiently sensitive that you get a real signal.”
With these updated SAFE-PAD results along with other studies, Dr. Parikh said, “If one weighs the risk benefit of cardiac lesion revascularization regarding requiring a repeat procedure vs. the risk of mortality from paclitaxel, if there is such a thing, I think most physicians have come back and the pendulum has swung back considering it reasonable to use paclitaxel products.”
That’s a message that will resonate with patients reluctant to return to the hospital since the COVID-19 outbreak, he said. “If you can tell them we can avoid a repeat trip to the hospital, they’re all for it,” Dr. Parikh said.
The study results were published simultaneously with Dr. Secemsky’s presentation. Funding for SAFE-PAD came from a multi-industry consortium consisting of BD, Boston Scientific, Cook Medical, Medtronic and Philips, which wasn’t involved in the study design or analysis.
Dr. Secemsky disclosed relationships with Abbott, BD, Bayer, Boston Scientific, Cook Medical, CSI, Endovascular Engineering, Inari, Janssen, Medtronic, Philips, and Venture Med. Dr. Parikh disclosed relationships with TriReme Medical, Boston Scientific, Heartflow, Cordis, Janssen, Terumo, Canon, Shockwave, Abiomed, Abbott, Cardiovascular Systems, Inari and Surmodics.
Patients who have paclitaxel-coated stents and balloons have survival and outcomes comparable to those who have a bare-metal stent or percutaneous transluminal angioplasty, according to updated results from a large study of almost 170,000 Medicare beneficiaries.
The SAFE-PAD study analyzed Medicare claims data of 168,533 patients, including 70,584 who were treated with drug-coated devices (DCD), from April 2015 through 2018.
Notably, Eric A. Secemsky, MD, MSc, said in an interview, that included more than 32,000 patients with more than 5 years of follow-up. He presented the results at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.
“What we’re seeing now with this study is that paclitaxel-coated devices [PCDs] have the same long-term survival compared to those treated with non–drug-coated devices (NDCDs),” said Dr. Secemsky, director of vascular intervention at Beth Israel Deaconess Medical Center in Boston. “I think this is another important piece and some of the longest-term data in this size population to demonstrate the long-term safety of PCD, and hopefully it will help us get back to normal practice that has been halted now for over 3 years.”
That was a reference to the 2018 meta-analysis by Konstantinos Katsanos, MD, PhD, of Patras University in Greece, and colleagues, which showed an increased risk of death after PCD placements. That study threw a wet blanket of sorts on PCD use, Dr. Secemsky said.
The median follow-up for SAFE-PAD (formally called the Safety Assessment of Femoropopliteal Endovascular treatment with Paclitaxel-coated Devices) was 3.5 years, with the longest follow-up, 6.3 years. The weighted cumulative incidence of mortality at 6.3 years was 63.6% with NDCDs and 62.5% with DCDs (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99; P < .0001). A subgroup analysis found no link between DCDs and increased death in low-risk patients, low-comorbid patients, inpatient or outpatient treatment, patients without critical limb ischemia, or patients treated with stents or balloon angioplasty alone.
“This report and the length of follow-up is one more piece that has continued to demonstrate safety with PCDs,” Dr. Secemsky said. He added that these results fall in line with smaller studies that failed to show a link between DCDs and long-term mortality, notably the SWEDEPAD randomized study of 2,289 patients evaluated through 4 years, and a subanalysis of 4,000 patients in VOYAGER-PAD through 42 months of follow-up.
“So we’ve really shown through these data sets and others that we can’t replicate any harms that we’ve seen in that Katsanos meta-analysis, and it suggests that there was some bias in that meta-analysis.”
Strengths of the study are its size and the way it followed the patients longitudinally, Sahil A. Parikh, MD, director of endovascular services at Columbia University Vagelos College of Physicians and Surgeons in New York, said in an interview.
With regard to its limitations, Dr. Parikh said, “On the other hand, it’s a claims database which doesn’t have the granularity about the patients’ specific procedural factors,” he said. “There are gaps that might further inform the value of lack thereof of the drug-coated device, but certainly at the topline, which is the hard endpoint of mortality, you can read quite a lot and you can assume that with such large numbers, the signal-to-noise ratio would be sufficiently sensitive that you get a real signal.”
With these updated SAFE-PAD results along with other studies, Dr. Parikh said, “If one weighs the risk benefit of cardiac lesion revascularization regarding requiring a repeat procedure vs. the risk of mortality from paclitaxel, if there is such a thing, I think most physicians have come back and the pendulum has swung back considering it reasonable to use paclitaxel products.”
That’s a message that will resonate with patients reluctant to return to the hospital since the COVID-19 outbreak, he said. “If you can tell them we can avoid a repeat trip to the hospital, they’re all for it,” Dr. Parikh said.
The study results were published simultaneously with Dr. Secemsky’s presentation. Funding for SAFE-PAD came from a multi-industry consortium consisting of BD, Boston Scientific, Cook Medical, Medtronic and Philips, which wasn’t involved in the study design or analysis.
Dr. Secemsky disclosed relationships with Abbott, BD, Bayer, Boston Scientific, Cook Medical, CSI, Endovascular Engineering, Inari, Janssen, Medtronic, Philips, and Venture Med. Dr. Parikh disclosed relationships with TriReme Medical, Boston Scientific, Heartflow, Cordis, Janssen, Terumo, Canon, Shockwave, Abiomed, Abbott, Cardiovascular Systems, Inari and Surmodics.
FROM SCAI 2022
Distal radial snuffbox technique comes up short in DISCO RADIAL
Distal radial access is not superior to conventional radial access with regard to radial artery occlusion (RAO) but is a valid alternative for use in percutaneous procedures, according to results of the DISCO RADIAL trial.
The primary endpoint of forearm RAO at discharge was not met, occurring in 0.31% of patients whose radial artery was accessed distally (DRA) at the anatomical snuffbox and in 0.91% of patients with conventional transradial access (TRA) in the intention-to-treat analysis (P = .29).
The DRA group was also twice as likely to crossover to another access point (7.5% vs. 3.7%; P = .002) and to experience radial artery spasm (5.4% vs. 2.7%; P < .015).
“The message first is that if you do a good job with transradial access you can end up with a lower [occlusion] rate,” said coprincipal investigator Adel Aminian, MD, Hôpital Civil Marie Curie, Charleroi, Belgium. “On the other hand, it’s a trade-off between a more demanding puncture for distal radial access but also a simpler hemostatic process, which I think is one of the main advantages of distal radial access.”
The results were presented during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, and published simultaneously in JACC: Cardiovascular Interventions.
DISCO-RADIAL (Distal Versus Conventional RADIAL Access for Coronary Angiography and Intervention) is the largest trial thus far to compare TRA with the distal radial snuffbox technique, which has shown promise for reducing RAO rates in the recent single-center randomized DAPRAO and ANGIE trials.
The trial was conducted at 15 sites across Europe and Japan in 1,309 patients with an indication for percutaneous coronary procedures using the 6Fr Glidesheath Slender (Terumo). The intention-to-treat population included 657 TRA patients and 650 DRA patients.
The two groups were well matched, with most having a chronic coronary syndrome. Operators had to have performed a minimum of 100 procedures by DRA and follow systematic best practices previously reported by the investigators to prevent RAO, Dr. Aminian said.
The use of DRA did not significantly affect the duration of the coronary procedure (27 minutes vs. 24 minutes with TRA; P = .12) or average radiation dose (1298 mGy vs. 1222 mGy; P = .70).
DRA, however, reduced the need for selective compression devices (88% vs. 99.2%) and shortened the median time to hemostasis from 180 minutes to 153 minutes (P for both < .001).
“These results establish compliance to best practice recommendations for RAO avoidance as a mandatory new reference in transradial practice,” Dr. Aminian concluded. “At the same time, distal radial artery arises as a valid alternative associated with higher crossover rates but with a simpler and shorter hemostasis process.”
A show of hands revealed that about 25% of the audience used distal radial access prior to the presentation but that enthusiasm fell off following the results.
Discussant Hany Eteiba, MD, Glasgow Royal Infirmary, said: “I salute your enthusiasm for presenting a negative trial and you tried to persuade the audience to use the distal radial artery results, but nonetheless.”
Dr. Eteiba said he could see a “potential advantage in the shorter hemostasis time,” and asked whether it might be influencing the rapid turnover for day-case angioplasty.
Dr. Aminian responded that “if you do an angioplasty you have to keep the patient for a certain amount of time, but I think for your nurse work and for the health care resources, having a very short hemostasis time is very interesting. We started with a hemostasis time of 2 hours and now we’ve decreased it to 1 hour and it will decrease even more.”
Session moderator Chaim Lotan, MD, Hadassah-Hebrew University Medical Center, Jerusalem, called DISCO-RADIAL an important study and said, “the question now is what’s the indication in your eyes for using distal radial?”
Dr. Aminian said that one message from the trial is that people who are using transradial access “have to do a better job,” and reminded the audience that RAO rates at many centers are too high, at 10% or upward.
At the same time, Dr. Aminian cautioned that operators wanting to use distal radial access “need to master the technique” or they will “end up with a relatively high failure rate.”
Discussant Eliano Navarese, MD, Nicolaus Copernicus University, Toruń, Poland, said, “I still think that it is a very valid approach, we use it for almost 20 years ... but it is very true, it is very demanding. And the learning curve of 100 cases in the trial maybe needed more cases.”
In an accompanying editorial, Grigorios Tsigkas, MD, PhD, University of Patras, Rio Patras, Greece, and colleagues wrote that the incidence of forearm RAO was “surprisingly low” but could be even lower if the authors administered adequate anticoagulation.
Still, they wrote that distal transradial access “for coronary procedures in combination with the systematic implementation of best practices for RAO prevention may be the final solution against RAO.”
The editorialists suggested that exposure to radiation could be the “main limitation of this novel vascular approach” and that forthcoming trials, such as DOSE, could shed light on this issue.
Increased procedure times in the DISCO RADIAL and ANGIE trials are secondary in stable patients, Dr. Tsigkas said, but could be a limitation in patients presenting with ST-segment elevation myocardial infarction (STEMI). Ongoing research, such as the RESERVE trial from China and a Korean trial, will provide insights into the safety and feasibility of distal transradial access in STEMI.
The study was supported by Terumo Europe. Dr. Aminian reported receiving honoraria or consultation fees from Abbott, Boston Scientific, and Terumo Interventional Systems. Dr. Tsigkas reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Distal radial access is not superior to conventional radial access with regard to radial artery occlusion (RAO) but is a valid alternative for use in percutaneous procedures, according to results of the DISCO RADIAL trial.
The primary endpoint of forearm RAO at discharge was not met, occurring in 0.31% of patients whose radial artery was accessed distally (DRA) at the anatomical snuffbox and in 0.91% of patients with conventional transradial access (TRA) in the intention-to-treat analysis (P = .29).
The DRA group was also twice as likely to crossover to another access point (7.5% vs. 3.7%; P = .002) and to experience radial artery spasm (5.4% vs. 2.7%; P < .015).
“The message first is that if you do a good job with transradial access you can end up with a lower [occlusion] rate,” said coprincipal investigator Adel Aminian, MD, Hôpital Civil Marie Curie, Charleroi, Belgium. “On the other hand, it’s a trade-off between a more demanding puncture for distal radial access but also a simpler hemostatic process, which I think is one of the main advantages of distal radial access.”
The results were presented during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, and published simultaneously in JACC: Cardiovascular Interventions.
DISCO-RADIAL (Distal Versus Conventional RADIAL Access for Coronary Angiography and Intervention) is the largest trial thus far to compare TRA with the distal radial snuffbox technique, which has shown promise for reducing RAO rates in the recent single-center randomized DAPRAO and ANGIE trials.
The trial was conducted at 15 sites across Europe and Japan in 1,309 patients with an indication for percutaneous coronary procedures using the 6Fr Glidesheath Slender (Terumo). The intention-to-treat population included 657 TRA patients and 650 DRA patients.
The two groups were well matched, with most having a chronic coronary syndrome. Operators had to have performed a minimum of 100 procedures by DRA and follow systematic best practices previously reported by the investigators to prevent RAO, Dr. Aminian said.
The use of DRA did not significantly affect the duration of the coronary procedure (27 minutes vs. 24 minutes with TRA; P = .12) or average radiation dose (1298 mGy vs. 1222 mGy; P = .70).
DRA, however, reduced the need for selective compression devices (88% vs. 99.2%) and shortened the median time to hemostasis from 180 minutes to 153 minutes (P for both < .001).
“These results establish compliance to best practice recommendations for RAO avoidance as a mandatory new reference in transradial practice,” Dr. Aminian concluded. “At the same time, distal radial artery arises as a valid alternative associated with higher crossover rates but with a simpler and shorter hemostasis process.”
A show of hands revealed that about 25% of the audience used distal radial access prior to the presentation but that enthusiasm fell off following the results.
Discussant Hany Eteiba, MD, Glasgow Royal Infirmary, said: “I salute your enthusiasm for presenting a negative trial and you tried to persuade the audience to use the distal radial artery results, but nonetheless.”
Dr. Eteiba said he could see a “potential advantage in the shorter hemostasis time,” and asked whether it might be influencing the rapid turnover for day-case angioplasty.
Dr. Aminian responded that “if you do an angioplasty you have to keep the patient for a certain amount of time, but I think for your nurse work and for the health care resources, having a very short hemostasis time is very interesting. We started with a hemostasis time of 2 hours and now we’ve decreased it to 1 hour and it will decrease even more.”
Session moderator Chaim Lotan, MD, Hadassah-Hebrew University Medical Center, Jerusalem, called DISCO-RADIAL an important study and said, “the question now is what’s the indication in your eyes for using distal radial?”
Dr. Aminian said that one message from the trial is that people who are using transradial access “have to do a better job,” and reminded the audience that RAO rates at many centers are too high, at 10% or upward.
At the same time, Dr. Aminian cautioned that operators wanting to use distal radial access “need to master the technique” or they will “end up with a relatively high failure rate.”
Discussant Eliano Navarese, MD, Nicolaus Copernicus University, Toruń, Poland, said, “I still think that it is a very valid approach, we use it for almost 20 years ... but it is very true, it is very demanding. And the learning curve of 100 cases in the trial maybe needed more cases.”
In an accompanying editorial, Grigorios Tsigkas, MD, PhD, University of Patras, Rio Patras, Greece, and colleagues wrote that the incidence of forearm RAO was “surprisingly low” but could be even lower if the authors administered adequate anticoagulation.
Still, they wrote that distal transradial access “for coronary procedures in combination with the systematic implementation of best practices for RAO prevention may be the final solution against RAO.”
The editorialists suggested that exposure to radiation could be the “main limitation of this novel vascular approach” and that forthcoming trials, such as DOSE, could shed light on this issue.
Increased procedure times in the DISCO RADIAL and ANGIE trials are secondary in stable patients, Dr. Tsigkas said, but could be a limitation in patients presenting with ST-segment elevation myocardial infarction (STEMI). Ongoing research, such as the RESERVE trial from China and a Korean trial, will provide insights into the safety and feasibility of distal transradial access in STEMI.
The study was supported by Terumo Europe. Dr. Aminian reported receiving honoraria or consultation fees from Abbott, Boston Scientific, and Terumo Interventional Systems. Dr. Tsigkas reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Distal radial access is not superior to conventional radial access with regard to radial artery occlusion (RAO) but is a valid alternative for use in percutaneous procedures, according to results of the DISCO RADIAL trial.
The primary endpoint of forearm RAO at discharge was not met, occurring in 0.31% of patients whose radial artery was accessed distally (DRA) at the anatomical snuffbox and in 0.91% of patients with conventional transradial access (TRA) in the intention-to-treat analysis (P = .29).
The DRA group was also twice as likely to crossover to another access point (7.5% vs. 3.7%; P = .002) and to experience radial artery spasm (5.4% vs. 2.7%; P < .015).
“The message first is that if you do a good job with transradial access you can end up with a lower [occlusion] rate,” said coprincipal investigator Adel Aminian, MD, Hôpital Civil Marie Curie, Charleroi, Belgium. “On the other hand, it’s a trade-off between a more demanding puncture for distal radial access but also a simpler hemostatic process, which I think is one of the main advantages of distal radial access.”
The results were presented during the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, and published simultaneously in JACC: Cardiovascular Interventions.
DISCO-RADIAL (Distal Versus Conventional RADIAL Access for Coronary Angiography and Intervention) is the largest trial thus far to compare TRA with the distal radial snuffbox technique, which has shown promise for reducing RAO rates in the recent single-center randomized DAPRAO and ANGIE trials.
The trial was conducted at 15 sites across Europe and Japan in 1,309 patients with an indication for percutaneous coronary procedures using the 6Fr Glidesheath Slender (Terumo). The intention-to-treat population included 657 TRA patients and 650 DRA patients.
The two groups were well matched, with most having a chronic coronary syndrome. Operators had to have performed a minimum of 100 procedures by DRA and follow systematic best practices previously reported by the investigators to prevent RAO, Dr. Aminian said.
The use of DRA did not significantly affect the duration of the coronary procedure (27 minutes vs. 24 minutes with TRA; P = .12) or average radiation dose (1298 mGy vs. 1222 mGy; P = .70).
DRA, however, reduced the need for selective compression devices (88% vs. 99.2%) and shortened the median time to hemostasis from 180 minutes to 153 minutes (P for both < .001).
“These results establish compliance to best practice recommendations for RAO avoidance as a mandatory new reference in transradial practice,” Dr. Aminian concluded. “At the same time, distal radial artery arises as a valid alternative associated with higher crossover rates but with a simpler and shorter hemostasis process.”
A show of hands revealed that about 25% of the audience used distal radial access prior to the presentation but that enthusiasm fell off following the results.
Discussant Hany Eteiba, MD, Glasgow Royal Infirmary, said: “I salute your enthusiasm for presenting a negative trial and you tried to persuade the audience to use the distal radial artery results, but nonetheless.”
Dr. Eteiba said he could see a “potential advantage in the shorter hemostasis time,” and asked whether it might be influencing the rapid turnover for day-case angioplasty.
Dr. Aminian responded that “if you do an angioplasty you have to keep the patient for a certain amount of time, but I think for your nurse work and for the health care resources, having a very short hemostasis time is very interesting. We started with a hemostasis time of 2 hours and now we’ve decreased it to 1 hour and it will decrease even more.”
Session moderator Chaim Lotan, MD, Hadassah-Hebrew University Medical Center, Jerusalem, called DISCO-RADIAL an important study and said, “the question now is what’s the indication in your eyes for using distal radial?”
Dr. Aminian said that one message from the trial is that people who are using transradial access “have to do a better job,” and reminded the audience that RAO rates at many centers are too high, at 10% or upward.
At the same time, Dr. Aminian cautioned that operators wanting to use distal radial access “need to master the technique” or they will “end up with a relatively high failure rate.”
Discussant Eliano Navarese, MD, Nicolaus Copernicus University, Toruń, Poland, said, “I still think that it is a very valid approach, we use it for almost 20 years ... but it is very true, it is very demanding. And the learning curve of 100 cases in the trial maybe needed more cases.”
In an accompanying editorial, Grigorios Tsigkas, MD, PhD, University of Patras, Rio Patras, Greece, and colleagues wrote that the incidence of forearm RAO was “surprisingly low” but could be even lower if the authors administered adequate anticoagulation.
Still, they wrote that distal transradial access “for coronary procedures in combination with the systematic implementation of best practices for RAO prevention may be the final solution against RAO.”
The editorialists suggested that exposure to radiation could be the “main limitation of this novel vascular approach” and that forthcoming trials, such as DOSE, could shed light on this issue.
Increased procedure times in the DISCO RADIAL and ANGIE trials are secondary in stable patients, Dr. Tsigkas said, but could be a limitation in patients presenting with ST-segment elevation myocardial infarction (STEMI). Ongoing research, such as the RESERVE trial from China and a Korean trial, will provide insights into the safety and feasibility of distal transradial access in STEMI.
The study was supported by Terumo Europe. Dr. Aminian reported receiving honoraria or consultation fees from Abbott, Boston Scientific, and Terumo Interventional Systems. Dr. Tsigkas reported having no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EUROPCR 2022
Keeping thyroid hormone treatment on target is key for the heart
A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.
“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.
Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.
“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
Getting the balance right: a tricky task
Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.
“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.
In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.
For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.
They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.
The mean age of participants was 67 years and 88.7% were male.
Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.
Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.
In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.
Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.
The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.
“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.
Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.
Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.
Addressing over- and under-treatment will avoid harm
The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.
And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.
“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.
Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.
“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.
“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.
“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.
“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.
Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.
“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
Getting the balance right: a tricky task
Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.
“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.
In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.
For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.
They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.
The mean age of participants was 67 years and 88.7% were male.
Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.
Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.
In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.
Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.
The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.
“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.
Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.
Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.
Addressing over- and under-treatment will avoid harm
The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.
And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.
“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.
Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.
“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.
“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.
“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study highlights the importance of avoiding both exogenous hyperthyroidism and exogenous hypothyroidism to decrease cardiovascular risk and death among patients receiving thyroid hormone treatment.
“Our findings suggest that clinicians should make every effort to maintain euthyroidism in patients on thyroid hormone treatment, regardless of underlying cardiovascular risk, particularly in vulnerable populations, such as older adults,” senior author Maria Papaleontiou, MD, said in an interview.
Commenting on the study, David S. Cooper, MD, of Johns Hopkins University School of Medicine, Baltimore, agreed that the findings are significant.
“Both undertreatment and overtreatment were associated with adverse cardiovascular outcomes, meaning that patients’ thyroid function needs to be monitored, and levothyroxine adjusted if need be, on an ongoing basis,” he told this news organization.
Getting the balance right: a tricky task
Variations in thyroid hormone levels falling above or below target ranges are common with thyroid hormone therapy, as a wide array of factors can prompt the need to regularly adjust dosing to maintain “index” levels. And while guidelines from the American Thyroid Association (ATA) recommend maintaining serum thyroid stimulating hormone (TSH) levels in the normal ranges during treatment, the task is tricky.
“Despite these [ATA] guidelines, prior studies in adults with hypothyroidism have shown that up to 30% are undertreated and up to 48% are overtreated,” said Dr. Papaleontiou, an assistant professor in the Division of Metabolism, Endocrinology at the University of Michigan, Ann Arbor.
In a previous study, Dr. Papaleontiou and colleagues showed that the intensity of thyroid hormone treatment is a modifiable risk factor for incident atrial fibrillation and stroke, however, less is understood about the association with cardiovascular mortality.
For the new study, published in JAMA Network Open, Josh M. Evron, MD, of the University of North Carolina, Chapel Hill, and colleagues further investigated the issue in a large, retrospective cohort of 705,307 adults in the Veterans Health Administration Corporate Data Warehouse treated with thyroid hormone during 2004-2017 who had a median follow-up of 4 years.
They investigated the roles of TSH as well as free thyroxine (FT4) levels among 701,929 adults in the group with data on TSH and 373,981 patients with FT4 measurements.
The mean age of participants was 67 years and 88.7% were male.
Over the course of the study, 10.8% of patients (75,963) died of cardiovascular causes.
Compared with patients with normal thyroid levels, those with exogenous hyperthyroidism related to thyroid hormone treatment had an increased risk of cardiovascular mortality, specifically including when TSH levels were below 0.1 mIU/L (adjusted hazard ratio, 1.39) and when FT4 levels were above 1.9 ng/dL (AHR, 1.29), independent of factors including age, sex, and traditional cardiovascular risk factors, including hypertension, smoking, and previous cardiovascular disease or arrhythmia.
In addition, the increased risk of cardiovascular mortality was observed with exogenous hypothyroidism, specifically among those with TSH levels above 20 mIU/L (AHR, 2.67) and FT4 levels below 0.7 ng/dL (AHR, 1.56), after multivariate adjustment.
Of note, the risk of cardiovascular mortality was dose-dependent, with the risk increasing progressively with the lower and higher TSH levels, compared with normal levels.
The increased mortality risk in relation to TSH levels was more pronounced among older patients, compared with FT4 associations, the authors note.
“From a clinical perspective, older adults, and particularly the oldest old (aged 85 years), appear to be the most vulnerable, with increased risk of cardiovascular mortality with both exogenous hyperthyroidism and hypothyroidism,” they report.
Among key limitations is that women, who make up the majority of patients with thyroid disease, are under-represented in the predominantly male population of the Veterans Health Administration.
Nevertheless, “because the risk of cardiovascular disease is higher for men than for women, and because more than 70,000 women were included in this cohort, the results of this study are highly clinically relevant,” the authors note.
Addressing over- and under-treatment will avoid harm
The results are also important considering the status of levothyroxine (for hypothyroidism) as consistently ranking among the top three prescription medications in the United States.
And with the common occurrence of exogenous hyperthyroidism or hypothyroidism, the findings have important implications.
“Addressing over- and under-treatment of hypothyroidism promptly will help reduce patient harm, particularly in vulnerable populations such as older adults who are at higher risk for adverse effects,” Dr. Papaleontiou said.
Dr. Cooper further commented that the findings underscore the need to be aware of treatment adjustments and targets that may vary according to patient age.
“In older persons, over 65-70, the target TSH may be higher [for example, 2-4 mIU/L] than in younger persons, and in patients above ages 70 or 80, serum TSH levels may be allowed to rise even further into the 4-6 mIU/L range,” he explained.
“The older the patient, the higher the chance for an adverse cardiovascular outcome if the TSH is subnormal due to iatrogenic thyrotoxicosis,” Dr. Cooper explained.
“In contrast, in younger individuals, an elevated TSH, indicating mild [subclinical] hypothyroidism may be associated with increased cardiovascular risk, especially with serum TSH levels greater than 7 mIU/L.”
The authors have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.