CAD & Atherosclerosis

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

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

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

‘Not all omega-3s created equal’

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

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

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

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

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

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

Placebo effects?

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

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

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

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

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

Still room for benefit?

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

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

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

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

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

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

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

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

Clinical inertia?

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

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

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

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

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

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

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

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

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

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

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

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

‘Not all omega-3s created equal’

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

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

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

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

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

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

Placebo effects?

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

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

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

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

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

Still room for benefit?

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

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

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

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

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

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

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

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

Clinical inertia?

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

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

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

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

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

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

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

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

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

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

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

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

‘Not all omega-3s created equal’

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

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

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

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

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

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

Placebo effects?

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

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

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

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

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

Still room for benefit?

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

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

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

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

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

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

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

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

Clinical inertia?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Prior observational reports

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

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

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

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

Long-term PPI use threatens harm

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

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

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

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

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

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

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

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

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

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

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

Prior observational reports

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

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

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

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

Long-term PPI use threatens harm

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

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

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

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

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

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

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

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

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

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

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

Prior observational reports

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

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

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

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

Long-term PPI use threatens harm

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

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

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

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

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

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

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

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

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

LDL triglycerides carry higher ASCVD risk

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

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

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

Results confirm hypothesis the study sought to disprove

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

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

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

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

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

Next step is finding a treatment

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

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

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

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

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

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

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

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

LDL triglycerides carry higher ASCVD risk

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

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

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

Results confirm hypothesis the study sought to disprove

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

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

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

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

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

Next step is finding a treatment

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

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

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

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

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

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

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

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

LDL triglycerides carry higher ASCVD risk

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

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

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

Results confirm hypothesis the study sought to disprove

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

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

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

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

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

Next step is finding a treatment

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

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

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

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

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.

But there are important general concepts to consider about this incident. These include ...

Cardiac arrest can happen to anyone

People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.

Survival turns on rapid and effective intervention

In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.

When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.

Need is an appropriate word in VF treatment

Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.

But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.

Bystanders must act

The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.

Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.

Widespread preparticipation screening of young athletes remains a bad idea

Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:

The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.

There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.

Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.

Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.

Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.

What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.

Conclusions

As long as there are sports, there will be athletes who suffer cardiac arrest.

We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.

John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.

But there are important general concepts to consider about this incident. These include ...

Cardiac arrest can happen to anyone

People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.

Survival turns on rapid and effective intervention

In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.

When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.

Need is an appropriate word in VF treatment

Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.

But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.

Bystanders must act

The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.

Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.

Widespread preparticipation screening of young athletes remains a bad idea

Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:

The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.

There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.

Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.

Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.

Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.

What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.

Conclusions

As long as there are sports, there will be athletes who suffer cardiac arrest.

We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.

John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The obvious first statement is that it’s neither wise nor appropriate to speculate on the specifics of Damar Hamlin’s cardiac event during a football game on Jan. 2 (including the possibility of commotio cordis) or his ongoing care. The public nature of his collapse induces intense curiosity but people with illness deserve privacy. Privacy in health care is in short supply. I disagree strongly with those who say his doctors ought to be giving public updates. That’s up to the family.

But there are important general concepts to consider about this incident. These include ...

Cardiac arrest can happen to anyone

People with structural heart disease or other chronic illnesses have a higher risk of arrhythmia, but the notion that athletes are immune from cardiac arrest is wrong. This sentence almost seems too obvious to write, but to this day, I hear clinicians express surprise that an athletic person has heart disease.

Survival turns on rapid and effective intervention

In the old days of electrophysiology, we used to test implantable cardioverter-defibrillators during an implant procedure by inducing ventricular fibrillation (VF) and watching the device convert it. Thankfully, trials have shown that this is no longer necessary for most implants.

When you induce VF In the EP lab, you learn quickly that a) it causes loss of consciousness in a matter of seconds, b) rapid defibrillation restores consciousness, often without the patients knowing or remembering they passed out, and c) the failure of the shock to terminate VF results in deterioration in a matter of 1-2 minutes. Even 1 minute in VF feels so long.

Need is an appropriate word in VF treatment

Clinicians often use the verb need. As in, this patient needs this pill or this procedure. It’s rarely appropriate.

But in the case of treating VF, patients truly need rapid defibrillation. Survival of out-of-hospital cardiac arrest is low because there just aren’t enough automated external defibrillators (AEDs) or people trained to use them. A study of patients who had out-of-hospital cardiac arrest in Denmark found that 30-day survival almost doubled (28.8% vs. 16.4%), when the nearest AED was accessible.

Bystanders must act

The public messages are simple: If a person loses consciousness in front of you, and is not breathing normally, assume it is a cardiac arrest, call 911 to get professional help, and start hands-only chest compressions. Don’t spend time checking for a pulse or trying to wake the person. If this is not a cardiac arrest, they will soon tell you to stop compressing their chest. Seconds matter.

Chest compressions are important but what is really needed is defibrillation. A crucial step in CPR is to send someone to get an AED and get the pads attached. If this is a shockable rhythm, deliver the shock. Hamlin’s collapse emphasizes the importance of the AED; without it, his survival to the hospital would have been unlikely.

Widespread preparticipation screening of young athletes remains a bad idea

Whenever cardiac arrest occurs in an athlete, in such a public way, people think about prevention. Surely it is better to prevent such an event than react to it, goes the thinking. The argument against this idea has four prongs:

The incidence of cardiac disease in a young athlete is extremely low, which sets up a situation where most “positive” tests are false positive. A false positive screening ECG or echocardiogram can create harm in multiple ways. One is the risk from downstream procedures, but worse is the inappropriate disqualification from sport. Healthwise, few harms could be greater than creating long-term fear of exercise in someone.

There is also the problem of false-negative screening tests. An ECG may be normal in the setting of hypertrophic cardiomyopathy. And a normal echocardiogram does not exclude arrhythmogenic right ventricular cardiomyopathy or other genetic causes of cardiac arrest. In a 2018 study from a major sports cardiology center in London, 6 of the 8 sudden cardiac deaths in their series were in athletes who had no detectable abnormalities on screening.

Even when disease is found, it’s not clear that prohibiting participation in sports prevents sudden death. Many previous class III recommendations against participation in sport now carry class II – may be considered – designations.

Finally, screening for any disease loses value as treatments improve. Public education regarding rapid intervention with CPR and AED use is the best treatment option. A great example is the case of Christian Erikson, a Danish soccer player who suffered cardiac arrest during a match at the European Championships in 2021 and was rapidly defibrillated on the field. Therapy was so effective that he was conscious and able to wave to fans on his way out of the stadium. He has now returned to elite competition.

Proponents of screening might oppose my take by saying that National Football League players are intensely screened. But this is different from widespread screening of high school and college athletes. It might sound harsh to say, but professional teams have dualities of interests in the health of their athletes given the million-dollar contracts.

What’s more, professional teams can afford to hire expert cardiologists to perform the testing. This would likely reduce the rate of false-positive findings, compared with screening in the community setting. I often have young people referred to me because of asymptomatic bradycardia found during athletic screening – an obviously normal finding.

Conclusions

As long as there are sports, there will be athletes who suffer cardiac arrest.

We can both hope for Hamlin’s full recovery and learn lessons to help reduce the rate of death from out-of-hospital cardiac arrest. This mostly involves education on how to help fellow humans and a public health commitment to access to AEDs.

John Mandrola, MD, practices cardiac electrophysiology in Louisville, Ky. and is a writer and podcaster for Medscape. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.

For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.

Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.

Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.

Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.

In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).

Still an important quality metric

STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.

“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.

Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.

“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.

Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”

The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.

However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
 

‘Suboptimal compliance’ with standards

The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.

“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.

“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.

“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”

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

Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.

For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.

Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.

Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.

Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.

In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).

Still an important quality metric

STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.

“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.

Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.

“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.

Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”

The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.

However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
 

‘Suboptimal compliance’ with standards

The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.

“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.

“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.

“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”

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

Therapy initiated within national treatment-time goals set a decade ago for patients with ST-segment elevation myocardial infarction (STEMI) remains associated with improved survival in recent years. But for many such patients, time from first symptoms to initiation of reperfusion therapy still fails to meet those goals, suggests a cross-sectional registry analysis.

For example, patients initially transported to centers with percutaneous coronary intervention (PCI) capability had a median treatment time of 148 minutes, in the analysis spanning the second quarter (Q2) of 2018 to the third quarter (Q3) of 2021. But the goal for centers called for treatment initiation within 90 minutes for at least 75% of such STEMI patients.

Moreover, overall STEMI treatment times and in-hospital mortality rose in tandem significantly from Q2 2018 through the first quarter (Q1) of 2021, which included the first year of the COVID-19 pandemic. Median time to treatment went from 86 minutes to 91 minutes during that period. Meanwhile, in-hospital mortality went from 5.6% to 8.7%, report the study authors led by James G. Jollis, MD, Duke University, Durham, N.C.

Their report, based on 114,871 STEMI patients at 601 US hospitals contributing to the Get With The Guidelines – Coronary Artery Disease registry, was published online in JAMA.

Of those patients, 25,085 had been transferred from non-PCI hospitals, 32,483 were walk-ins, and 57,303 arrived via emergency medical services (EMS). Their median times from symptom onset to PCI were 240, 195, and 148 minutes, respectively.

In-hospital mortality was significantly reduced in an adjusted analysis for patients treated within target times, compared with those whose treatment missed the time goals, regardless of whether they were transported by EMS, walked into a hospital with on-site PCI, or were transferred from a non-PCI center (Table 1).

Still an important quality metric

STEMI treatment times remain an important quality metric to which hospitals should continue to pay attention because shorter times improve patient care, Deepak Bhatt, MD, MPH, told this news organization.

“Having said that, as with all metrics, one needs to be thoughtful and realize that a difference of a couple of minutes is probably not a crucial thing,” said Dr. Bhatt, Brigham and Women’s Hospital and Harvard Medical School, Boston, who was not involved with the current study.

Interhospital transfers indeed involve longer delays, he observed, suggesting that regional integrated health systems should develop methods for optimizing STEMI care – even, for example, if they involve bypassing non-PCI centers or stopping patients briefly for stabilization followed by rapid transport to a PCI-capable facility.

“That, of course, requires cooperation among hospitals. Sometimes that requires hospitals putting aside economic considerations and just focusing on doing the right thing for that individual patient,” Dr. Bhatt said.

Transfer delays are common for patients presenting with STEMI at hospitals without PCI capability, he noted. “Having clear protocols in place that expedite that type of transfer, I think, could go a long way in reducing the time to treatment in patients that are presenting to the hospital without cath labs. That’s an important message that these data provide.”

The onset of COVID-19 led to widespread delays in STEMI time to treatment early in the pandemic. There were concerns about exposing cath lab personnel to SARS-CoV-2 and potential adverse consequences of sick personnel being unable to provide patient care in the subsequent weeks and months, Dr. Bhatt observed.

However, “All of that seems to have quieted down, and I don’t think COVID is impacting time to treatment right now.”
 

‘Suboptimal compliance’ with standards

The current findings of “suboptimal compliance with national targets underscore why reassessing quality metrics, in light of changing practice patterns and other secular trends, is critical,” write Andrew S. Oseran, MD, MBA, and Robert W. Yeh, MD, both of Harvard Medical School, in an accompanying editorial.

“While the importance of coordinated and expeditious care for this high-risk patient population is undeniable, the specific actions that hospitals can – or should – take to further improve overall STEMI outcomes are less clear,” they say.

“As physicians contemplate the optimal path forward in managing the care of STEMI patients, they must recognize the clinical and operational nuance that exists in caring for this diverse population and acknowledge the trade-offs associated with uniform quality metrics,” write the editorialists.

“Global reductions in time to treatment for STEMI patients has been one of health care’s great success stories. As we move forward, it may be time to consider whether efforts to achieve additional improvement in target treatment times will result in substantive benefits, or whether we have reached the point of diminishing returns.”

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

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

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

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

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

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

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

Irregular and especially long menstrual cycles, particularly in early and mid adulthood, are associated with an increased risk for cardiovascular disease. This finding is demonstrated in a new analysis of the Nurses’ Health Study II.

“To date, several studies have reported increased risks of cardiovascular risk factors or cardiovascular disease in connection with cycle disorders,” Yi-Xin Wang, MD, PhD, a research fellow in nutrition, and associates from the Harvard School of Public Health, Boston, wrote in an article published in JAMA Network Open.

Ute Seeland, MD, speaker of the Gender Medicine in Cardiology Working Group of the German Cardiology Society, said in an interview“We know that women who have indicated in their medical history that they have irregular menstrual cycles, invariably in connection with polycystic ovary syndrome (PCOS), more commonly develop diabetes and other metabolic disorders, as well as cardiovascular diseases.”
 

Cycle disorders’ role

However, the role that irregular or especially long cycles play at different points of a woman’s reproductive life span was unclear. Therefore, the research group investigated the associations in the Nurses’ Health Study II between cycle irregularity and cycle length in women of different age groups who later experienced cardiovascular events.

At the end of this study in 1989, the participants also provided information regarding the length and irregularity of their menstrual cycle from ages 14 to 17 years and again from ages 18 to 22 years. The information was updated in 1993 when the participants were aged 29-46 years. The data from 2019 to 2022 were analyzed.

“This kind of long-term cohort study is extremely rare and therefore something special,” said Dr. Seeland, who conducts research at the Institute for Social Medicine, Epidemiology, and Health Economics at the Charité – University Hospital Berlin.

The investigators used the following cycle classifications: very regular (no more than 3 or 4 days before or after the expected date), regular (within 5-7 days), usually irregular, always irregular, or no periods.

The cycle lengths were divided into the following categories: less than 21 days, 21-25 days, 26-31 days, 32-39 days, 40-50 days, more than 50 days, and too irregular to estimate the length.

The onset of cardiovascular diseases was determined using information from the participants and was confirmed by reviewing the medical files. Relevant to the study were lethal and nonlethal coronary heart diseases (such as myocardial infarction or coronary artery revascularization), as well as strokes.
 

Significant in adulthood

The data from 80,630 study participants were included in the analysis. At study inclusion, the average age of the participants was 37.7 years, and the average body mass index (BMI) was 25.1. “Since it was predominantly White nurses who took part in the study, the data are not transferable to other, more diverse populations,” said Dr. Seeland.

Over 24 years, 1,816 women (2.4%) had a cardiovascular event. “We observed an increased rate of cardiovascular events in women with an irregular cycle and longer cycle, both in early an in mid-adulthood,” wrote Dr. Wang and associates. “Similar trends were also observed for cycle disorders when younger, but this association was weaker than in adulthood.”

Compared with women with very regular cycles, women with irregular cycles or without periods who were aged 14-17 years, 18-22 years, or 29-49 years exhibited a 15%, 36%, and 40% higher risk of a cardiovascular event, respectively.

Similarly, women aged 18-22 years or 29-46 years with long cycles of 40 days or more had a 44% or 30% higher risk of cardiovascular disease, respectively, compared with women with cycle lengths of 26-31 days.

“The coronary heart diseases were decisive for the increase, and less so, the strokes,” wrote the researchers.
 

Classic risk factors?

Dr. Seeland praised the fact that the study authors tried to determine the role that classic cardiovascular risk factors played. “Compared with women with a regular cycle, women with an irregular cycle had a higher BMI, more frequently increased cholesterol levels, and an elevated blood pressure,” she said. Women with a long cycle displayed a similar pattern.

It can be assumed from this that over a woman’s life span, BMI affects the risk of cardiovascular disease. Therefore, Dr. Wang and coauthors adjusted the results on the basis of BMI, which varies over time.

Regarding other classic risk factors that may have played a role, “hypercholesterolemia, chronic high blood pressure, and type 2 diabetes were only responsible in 5.4%-13.5% of the associations,” wrote the researchers.

“Our results suggest that certain characteristics of the menstrual cycle across a woman’s reproductive lifespan may constitute additional risk markers for cardiovascular disease,” according to the authors.

The highest rates of cardiovascular disease were among women with permanently irregular or long cycles in early to mid adulthood, as well as women who had regular cycles when younger but had irregular cycles in mid adulthood. “This indicates that the change from one cycle phenotype to another could be a surrogate marker for metabolic changes, which in turn contribute to the formation of cardiovascular diseases,” wrote the authors.

The study was observational and so conclusions cannot be drawn regarding causal relationships. But Dr. Wang and associates indicate that the most common cause of an irregular menstrual cycle may be PCOS. “Roughly 90% of women with cycle disorders or oligomenorrhea have signs of PCOS. And it was shown that women with PCOS have an increased risk of cardiovascular disease.”

They concluded that “the associations observed between irregular and long cycles in early to mid-adulthood and cardiovascular diseases are likely attributable to underlying PCOS.”

For Dr. Seeland, however, this conclusion is “too monocausal. At no point in time did there seem to be any direct information regarding the frequency of PCOS during the data collection by the respondents.”

For now, we can only speculate about the mechanisms. “The association between a very irregular and long cycle and the increased risk of cardiovascular diseases has now only been described. More research should be done on the causes,” said Dr. Seeland.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Irregular and especially long menstrual cycles, particularly in early and mid adulthood, are associated with an increased risk for cardiovascular disease. This finding is demonstrated in a new analysis of the Nurses’ Health Study II.

“To date, several studies have reported increased risks of cardiovascular risk factors or cardiovascular disease in connection with cycle disorders,” Yi-Xin Wang, MD, PhD, a research fellow in nutrition, and associates from the Harvard School of Public Health, Boston, wrote in an article published in JAMA Network Open.

Ute Seeland, MD, speaker of the Gender Medicine in Cardiology Working Group of the German Cardiology Society, said in an interview“We know that women who have indicated in their medical history that they have irregular menstrual cycles, invariably in connection with polycystic ovary syndrome (PCOS), more commonly develop diabetes and other metabolic disorders, as well as cardiovascular diseases.”
 

Cycle disorders’ role

However, the role that irregular or especially long cycles play at different points of a woman’s reproductive life span was unclear. Therefore, the research group investigated the associations in the Nurses’ Health Study II between cycle irregularity and cycle length in women of different age groups who later experienced cardiovascular events.

At the end of this study in 1989, the participants also provided information regarding the length and irregularity of their menstrual cycle from ages 14 to 17 years and again from ages 18 to 22 years. The information was updated in 1993 when the participants were aged 29-46 years. The data from 2019 to 2022 were analyzed.

“This kind of long-term cohort study is extremely rare and therefore something special,” said Dr. Seeland, who conducts research at the Institute for Social Medicine, Epidemiology, and Health Economics at the Charité – University Hospital Berlin.

The investigators used the following cycle classifications: very regular (no more than 3 or 4 days before or after the expected date), regular (within 5-7 days), usually irregular, always irregular, or no periods.

The cycle lengths were divided into the following categories: less than 21 days, 21-25 days, 26-31 days, 32-39 days, 40-50 days, more than 50 days, and too irregular to estimate the length.

The onset of cardiovascular diseases was determined using information from the participants and was confirmed by reviewing the medical files. Relevant to the study were lethal and nonlethal coronary heart diseases (such as myocardial infarction or coronary artery revascularization), as well as strokes.
 

Significant in adulthood

The data from 80,630 study participants were included in the analysis. At study inclusion, the average age of the participants was 37.7 years, and the average body mass index (BMI) was 25.1. “Since it was predominantly White nurses who took part in the study, the data are not transferable to other, more diverse populations,” said Dr. Seeland.

Over 24 years, 1,816 women (2.4%) had a cardiovascular event. “We observed an increased rate of cardiovascular events in women with an irregular cycle and longer cycle, both in early an in mid-adulthood,” wrote Dr. Wang and associates. “Similar trends were also observed for cycle disorders when younger, but this association was weaker than in adulthood.”

Compared with women with very regular cycles, women with irregular cycles or without periods who were aged 14-17 years, 18-22 years, or 29-49 years exhibited a 15%, 36%, and 40% higher risk of a cardiovascular event, respectively.

Similarly, women aged 18-22 years or 29-46 years with long cycles of 40 days or more had a 44% or 30% higher risk of cardiovascular disease, respectively, compared with women with cycle lengths of 26-31 days.

“The coronary heart diseases were decisive for the increase, and less so, the strokes,” wrote the researchers.
 

Classic risk factors?

Dr. Seeland praised the fact that the study authors tried to determine the role that classic cardiovascular risk factors played. “Compared with women with a regular cycle, women with an irregular cycle had a higher BMI, more frequently increased cholesterol levels, and an elevated blood pressure,” she said. Women with a long cycle displayed a similar pattern.

It can be assumed from this that over a woman’s life span, BMI affects the risk of cardiovascular disease. Therefore, Dr. Wang and coauthors adjusted the results on the basis of BMI, which varies over time.

Regarding other classic risk factors that may have played a role, “hypercholesterolemia, chronic high blood pressure, and type 2 diabetes were only responsible in 5.4%-13.5% of the associations,” wrote the researchers.

“Our results suggest that certain characteristics of the menstrual cycle across a woman’s reproductive lifespan may constitute additional risk markers for cardiovascular disease,” according to the authors.

The highest rates of cardiovascular disease were among women with permanently irregular or long cycles in early to mid adulthood, as well as women who had regular cycles when younger but had irregular cycles in mid adulthood. “This indicates that the change from one cycle phenotype to another could be a surrogate marker for metabolic changes, which in turn contribute to the formation of cardiovascular diseases,” wrote the authors.

The study was observational and so conclusions cannot be drawn regarding causal relationships. But Dr. Wang and associates indicate that the most common cause of an irregular menstrual cycle may be PCOS. “Roughly 90% of women with cycle disorders or oligomenorrhea have signs of PCOS. And it was shown that women with PCOS have an increased risk of cardiovascular disease.”

They concluded that “the associations observed between irregular and long cycles in early to mid-adulthood and cardiovascular diseases are likely attributable to underlying PCOS.”

For Dr. Seeland, however, this conclusion is “too monocausal. At no point in time did there seem to be any direct information regarding the frequency of PCOS during the data collection by the respondents.”

For now, we can only speculate about the mechanisms. “The association between a very irregular and long cycle and the increased risk of cardiovascular diseases has now only been described. More research should be done on the causes,” said Dr. Seeland.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Irregular and especially long menstrual cycles, particularly in early and mid adulthood, are associated with an increased risk for cardiovascular disease. This finding is demonstrated in a new analysis of the Nurses’ Health Study II.

“To date, several studies have reported increased risks of cardiovascular risk factors or cardiovascular disease in connection with cycle disorders,” Yi-Xin Wang, MD, PhD, a research fellow in nutrition, and associates from the Harvard School of Public Health, Boston, wrote in an article published in JAMA Network Open.

Ute Seeland, MD, speaker of the Gender Medicine in Cardiology Working Group of the German Cardiology Society, said in an interview“We know that women who have indicated in their medical history that they have irregular menstrual cycles, invariably in connection with polycystic ovary syndrome (PCOS), more commonly develop diabetes and other metabolic disorders, as well as cardiovascular diseases.”
 

Cycle disorders’ role

However, the role that irregular or especially long cycles play at different points of a woman’s reproductive life span was unclear. Therefore, the research group investigated the associations in the Nurses’ Health Study II between cycle irregularity and cycle length in women of different age groups who later experienced cardiovascular events.

At the end of this study in 1989, the participants also provided information regarding the length and irregularity of their menstrual cycle from ages 14 to 17 years and again from ages 18 to 22 years. The information was updated in 1993 when the participants were aged 29-46 years. The data from 2019 to 2022 were analyzed.

“This kind of long-term cohort study is extremely rare and therefore something special,” said Dr. Seeland, who conducts research at the Institute for Social Medicine, Epidemiology, and Health Economics at the Charité – University Hospital Berlin.

The investigators used the following cycle classifications: very regular (no more than 3 or 4 days before or after the expected date), regular (within 5-7 days), usually irregular, always irregular, or no periods.

The cycle lengths were divided into the following categories: less than 21 days, 21-25 days, 26-31 days, 32-39 days, 40-50 days, more than 50 days, and too irregular to estimate the length.

The onset of cardiovascular diseases was determined using information from the participants and was confirmed by reviewing the medical files. Relevant to the study were lethal and nonlethal coronary heart diseases (such as myocardial infarction or coronary artery revascularization), as well as strokes.
 

Significant in adulthood

The data from 80,630 study participants were included in the analysis. At study inclusion, the average age of the participants was 37.7 years, and the average body mass index (BMI) was 25.1. “Since it was predominantly White nurses who took part in the study, the data are not transferable to other, more diverse populations,” said Dr. Seeland.

Over 24 years, 1,816 women (2.4%) had a cardiovascular event. “We observed an increased rate of cardiovascular events in women with an irregular cycle and longer cycle, both in early an in mid-adulthood,” wrote Dr. Wang and associates. “Similar trends were also observed for cycle disorders when younger, but this association was weaker than in adulthood.”

Compared with women with very regular cycles, women with irregular cycles or without periods who were aged 14-17 years, 18-22 years, or 29-49 years exhibited a 15%, 36%, and 40% higher risk of a cardiovascular event, respectively.

Similarly, women aged 18-22 years or 29-46 years with long cycles of 40 days or more had a 44% or 30% higher risk of cardiovascular disease, respectively, compared with women with cycle lengths of 26-31 days.

“The coronary heart diseases were decisive for the increase, and less so, the strokes,” wrote the researchers.
 

Classic risk factors?

Dr. Seeland praised the fact that the study authors tried to determine the role that classic cardiovascular risk factors played. “Compared with women with a regular cycle, women with an irregular cycle had a higher BMI, more frequently increased cholesterol levels, and an elevated blood pressure,” she said. Women with a long cycle displayed a similar pattern.

It can be assumed from this that over a woman’s life span, BMI affects the risk of cardiovascular disease. Therefore, Dr. Wang and coauthors adjusted the results on the basis of BMI, which varies over time.

Regarding other classic risk factors that may have played a role, “hypercholesterolemia, chronic high blood pressure, and type 2 diabetes were only responsible in 5.4%-13.5% of the associations,” wrote the researchers.

“Our results suggest that certain characteristics of the menstrual cycle across a woman’s reproductive lifespan may constitute additional risk markers for cardiovascular disease,” according to the authors.

The highest rates of cardiovascular disease were among women with permanently irregular or long cycles in early to mid adulthood, as well as women who had regular cycles when younger but had irregular cycles in mid adulthood. “This indicates that the change from one cycle phenotype to another could be a surrogate marker for metabolic changes, which in turn contribute to the formation of cardiovascular diseases,” wrote the authors.

The study was observational and so conclusions cannot be drawn regarding causal relationships. But Dr. Wang and associates indicate that the most common cause of an irregular menstrual cycle may be PCOS. “Roughly 90% of women with cycle disorders or oligomenorrhea have signs of PCOS. And it was shown that women with PCOS have an increased risk of cardiovascular disease.”

They concluded that “the associations observed between irregular and long cycles in early to mid-adulthood and cardiovascular diseases are likely attributable to underlying PCOS.”

For Dr. Seeland, however, this conclusion is “too monocausal. At no point in time did there seem to be any direct information regarding the frequency of PCOS during the data collection by the respondents.”

For now, we can only speculate about the mechanisms. “The association between a very irregular and long cycle and the increased risk of cardiovascular diseases has now only been described. More research should be done on the causes,” said Dr. Seeland.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

Leading cardiology societies have issued a “call for action” on a global scale to reinvent randomized clinical trials fit for the 21st century.

“Randomized trials are an essential tool for reliably assessing the effects of treatments, but they have become too costly and too burdensome,” first author Louise Bowman, University of Oxford, England, told this news organization. “We urgently need to modernize our approach to clinical trials in order to continue to improve patient care.”

The joint opinion is from the European Society of Cardiology, the American Heart Association, the American College of Cardiology, and the World Heart Federation. It was simultaneously published online in the European Heart Journal, Circulation, Journal of the American College of Cardiology, and Global Heart.

The authors note that the availability of large-scale “real-world” data is increasingly being touted as a way to bypass the challenges of conducting randomized trials. Yet, observational analyses of real-world data “are not a suitable alternative to randomization,” Prof. Bowman said.

Cardiology has historically led the way in transforming clinical practice with groundbreaking “mega-trials,” such as the International Study of Infarct Survival (ISIS), Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto (GISSI), and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO).

But over the past 25 years, there has been a huge increase in the rules and related bureaucracy governing clinical trials, which hinders the ability to conduct trials swiftly and affordably, the authors point out.

The COVID-19 pandemic has shown that important clinical trials can be performed quickly and efficiently in busy hospitals, they note.

“The RECOVERY trial in COVID-19 has been an excellent example of this, with results that are estimated to have saved around 1 million lives worldwide within just 1 year,” Prof. Bowman told this news organization.

A Good Clinical Trials Collaborative made up of key stakeholders recently developed new guidelines designed to promote better, more efficient randomized controlled trials.

“If widely adopted and used alongside valuable 21st century electronic health records, we could transform the clinical trials landscape and do many more high-quality trials very cost-effectively,” Prof. Bowman said.

“Widespread adoption and implementation of the revised guidelines will require collaboration with a wide range of national and international organizations, including patient, professional, academic, and industry groups, funders and government organizations, and ethics, health policy, and regulatory bodies,” Prof. Bowman acknowledged.

“This is work that the Good Clinical Trials Collaborative is leading. It is hoped that this endorsement by the joint cardiovascular societies will increase awareness and provide valuable support to his important work,” she added.

No commercial funding was received. The authors have disclosed no relevant financial relationships.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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

High levels of lipoprotein(a) increase the risk for incident cardiovascular disease (CVD) for hypertensive individuals but not for those without hypertension, a new MESA analysis suggests.

There are ways to test for statistical interaction, “in this case, multiplicative interaction between Lp(a) and hypertension, which suggests that Lp(a) is actually modifying the effect between blood pressure and cardiovascular disease. It’s not simply additive,” senior author Michael D. Shapiro, DO, Wake Forest University, Winston-Salem, N.C., told this news organization.

“So that’s new and I don’t think anybody’s looked at that before.”

Although Lp(a) is recognized as an independent cause of atherosclerotic CVD (ASCVD), the significance of Lp(a) in hypertension has been “virtually untapped,” he noted. A recent prospective study reported that elevated CVD risk was present only in individuals with Lp(a) ≥ 30 mg/dL and hypertension but it included only Chinese participants with stable coronary artery disease.

The current analysis, published online in the journal Hypertension, included 6,674 participants in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), all free of baseline ASCVD, who were recruited from six communities in the United States and had measured baseline Lp(a), blood pressure, and CVD events data over follow-up from 2000 to 2018.

Participants were stratified into four groups based on the presence or absence of hypertension (defined as 140/90 mm Hg or higher or the use of antihypertensive drugs) and an Lp(a) threshold of 50 mg/dL, as recommended by the American College of Cardiology/American Heart Association cholesterol guideline for consideration as an ASCVD risk-enhancing factor.

Slightly more than half of participants were female (52.8%), 38.6% were White, 27.5% were African American, 22.1% were Hispanic, and 11.9% were Chinese American.

According to the researchers, 809 participants had a CVD event over an average follow-up of 13.9 years, including 7.7% of group 1 with Lp(a) < 50 mg/dL and no hypertension, 8.0% of group 2 with Lp(a) ≥ 50 mg/dL and no hypertension, 16.2% of group 3 with Lp(a) < 50 mg/dL and hypertension, and 18.8% of group 4 with Lp(a) ≥ 50 mg/dL and hypertension.

When compared with group 1 in a fully adjusted Cox proportional model, participants with elevated Lp(a) and no hypertension (group 2) did not have an increased risk of CVD events (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.79-1.50).

CVD risk, however, was significantly higher in group 3 with normal Lp(a) and hypertension (HR, 1.66; 95% CI, 1.39-1.98) and group 4 with elevated Lp(a) and hypertension (HR, 2.07, 95% CI, 1.63-2.62).

Among all participants with hypertension (groups 3 and 4), Lp(a) was associated with a significant increase in CVD risk (HR, 1.24, 95% CI, 1.01-1.53).

“What I think is interesting here is that in the absence of hypertension, we didn’t really see an increased risk despite having an elevated Lp(a),” said Dr. Shapiro. “What it may indicate is that really for Lp(a) to be associated with risk, there may already need to be some kind of arterial damage that allows the Lp(a) to have its atherogenic impact.

“In other words, in individuals who have totally normal arterial walls, potentially, maybe that is protective enough against Lp(a) that in the absence of any other injurious factor, maybe it’s not an issue,” he said. “That’s a big hypothesis-generating [statement], but hypertension is certainly one of those risk factors that’s known to cause endothelial injury and endothelial dysfunction.”

Dr. Shapiro pointed out that when first measured in MESA, Lp(a) was measured in 4,600 participants who were not on statins, which is important because statins can increase Lp(a) levels.

“When you look just at those participants, those 4,600, you actually do see a relationship between Lp(a) and cardiovascular disease,” he said. “When you look at the whole population, including the 17% who are baseline populations, even when you adjust for statin therapy, we fail to see that, at least in the long-term follow up.”

Nevertheless, he cautioned that hypertension is just one of many traditional cardiovascular risk factors that could affect the relationship between Lp(a) and CVD risk. “I don’t want to suggest that we believe there’s something specifically magical about hypertension and Lp(a). If we chose, say, diabetes or smoking or another traditional risk factor, we may or may not have seen kind of similar results.”

When the investigators stratified the analyses by sex and race/ethnicity, they found that Lp(a) was not associated with CVD risk, regardless of hypertension status. In Black participants, however, greater CVD risk was seen when both elevated Lp(a) and hypertension were present (HR, 2.07, 95% CI, 1.34-3.21; P = .001).

Asked whether the results support one-time universal screening for Lp(a), which is almost exclusively genetically determined, Dr. Shapiro said he supports screening but that this was a secondary analysis and its numbers were modest. He added that median Lp(a) level is higher in African Americans than any other racial/ethnic group but the “most recent data has clarified that, per any absolute level of Lp(a), it appears to confer the same absolute risk in any racial or ethnic group.”

The authors acknowledge that differential loss to follow-up could have resulted in selection bias in the study and that there were relatively few CVD events in group 2, which may have limited the ability to detect differences in groups without hypertension, particularly in the subgroup analyses. Other limitations are the potential for residual confounding and participants may have developed hypertension during follow-up, resulting in misclassification bias.

Further research is needed to better understand the mechanistic link between Lp(a), hypertension, and CVD, Dr. Shapiro said. Further insights also should be provided by the ongoing phase 3 Lp(a) HORIZON trial evaluating the effect of Lp(a) lowering with the investigational antisense drug, pelacarsen, on cardiovascular events in 8,324 patients with established CVD and elevated Lp(a). The study is expected to be completed in May 2025.

The study was supported by contracts from the National Heart, Lung, and Blood Institute and by grants from the National Center for Advanced Translational Sciences. Dr. Shapiro reports participating in scientific advisory boards with Amgen, Novartis, and Novo Nordisk, and consulting for Regeneron.

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