Sue Hughes

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new study has provided further reassurance on questions about the risk of intracerebral hemorrhage (ICH) with statins.

The Danish case-control study, which compared statin use in 2,164 case patients with ICH and in 86,255 matched control persons, found that current statin use was associated with a lower risk of having a first ICH and that the risk was further reduced with longer duration of statin use.

The study also showed that statin use was linked to a lower risk of ICH in the more superficial lobar areas of the brain and in the deeper, nonlobar locations. There was no difference in the magnitude of risk reduction between the two locations.

“Although this study is observational, I feel these data are strong, and the results are reassuring. It certainly does not suggest any increased risk of ICH with statins,” senior author David Gaist, PhD, Odense University Hospital, Denmark, said in an interview.

“On the contrary, it indicates a lower risk, which seems to be independent of the location of the bleed.”

The study was published online in Neurology.

The authors note that statins effectively reduce the occurrence of cardiovascular events and ischemic stroke in high-risk populations, but early randomized trials raised concerns of an increased risk of ICH among statin users who have a history of stroke.

Subsequent observational studies, including four meta-analyses, included patients with and those without prior stroke. The results were inconsistent, although most found no increase in bleeding. More recent studies have found a lower risk of ICH among statin users; the risk was inversely associated with the duration and intensity of statin treatment.

However, the researchers point out that few studies have assessed the association between statin use and the location of ICH. Hemorrhages that occur in the lobar region of the brain and those that occur in the nonlobar areas can have different pathophysiologies. Arteriolosclerosis, which is strongly associated with hypertension, is a common histologic finding in patients with ICH, regardless of hemorrhage location, while cerebral amyloid angiopathy (CAA) is associated with lobar but not nonlobar ICH.

The current study was conducted to look more closely at the relationship between statin use and hematoma location as a reflection of differences in the underlying pathophysiologies of lobar versus nonlobar ICH.

The researchers used Danish registries to identify all first-ever cases of spontaneous ICH that occurred between 2009 and 2018 in persons older than 55 years in the Southern Denmark region. Patients with traumatic ICH or ICH related to vascular malformations and tumors were excluded.

These cases were verified through medical records. ICH diagnoses were classified as having a lobar or nonlobar location, and patients were matched for age, sex, and calendar year to general population control persons. The nationwide prescription registry was also analyzed to ascertain use of statins and other medications.

The study included 989 patients with lobar ICH who were matched to 39,500 control persons and 1,175 patients with nonlobar ICH who were matched to 46,755 control persons.

Results showed that current statin use was associated with a 16%-17% relative reduction in ICH risk. There was no difference with respect to ICH location.

For lobar ICH, statin use showed an adjusted odds ratio of 0.83 (95% confidence interval, 0.70-0.98); for nonlobar ICH, the adjusted odds ratio was 0.84 (95% CI, 0.72-0.98).

Longer duration of statin use was associated with a greater reduction in risk of ICH; use for more than 5 years was associated with a relative reduction of ICH of 33%-38%, again with no difference with regard to ICH location.

For lobar ICH, statin use for more than 5 years showed an adjusted odds ratio of 0.67 (95% CI, 0.51-0.87); and for nonlobar ICH, the adjusted odds ratio was 0.62 (95% CI, 0.48-0.80).

“We suspected that statins may have more of an effect in reducing nonlobar ICH, as this type is considered to be more associated with arteriosclerosis, compared with lobar ICH,” Dr. Gaist explained. “But we didn’t find that. We found that taking statins was associated with a similar reduction in risk of both lobar and nonlobar ICH.”

Although amyloid angiopathy can contribute to lobar ICH, arteriosclerosis is still involved in the majority of cases, he noted. He cited a recent population-based U.K. study that showed that while histologically verified CAA was present in 58% of patients with a lobar ICH, most also had evidence of arteriosclerosis, with only 13% having isolated CAA pathology.

“If statins exert their effect on reducing ICH by reducing arteriosclerosis, which is likely, then this observation of arteriosclerosis pathology being prevalent in both lobar and nonlobar ICH locations would explain our results,” Dr. Gaist commented.

“Strengths of our study include the large numbers involved and the fact that the patients are unselected. We tried to find everyone who had had a first ICH in a well-defined region of Denmark, so issues of selection are less of a concern than in some other studies,” he noted.

He also pointed out that all the ICH diagnoses were verified from medical records and that in a substudy, brain scans were evaluated, with investigators masked to clinical data to evaluate the location and characteristics of the hematoma. In addition, data on statin use were collected prospectively from a nationwide prescription registry.
 

Interaction with antihypertensives, anticoagulants?

Other results from the study suggest a possible interaction between statin use and antihypertensive and anticoagulant drugs.

Data showed that the lower ICH risk was restricted to patients who received statins and antihypertensive drugs concurrently. Conversely, only patients who were not concurrently taking anticoagulants had a lower risk of ICH in association with statin use.

Dr. Gaist suggested that the lack of a reduction in ICH with statins among patients taking anticoagulants could be because the increased risk of ICH with anticoagulants was stronger than the reduced risk with statins.

Regarding the fact that the reduced risk of ICH with statins was only observed among individuals who were also taking antihypertensive medication, Dr. Gaist noted that because hypertension is such an important risk factor for ICH, “it may be that to get the true benefit of statins, patients have to have their hypertension controlled.”

However, an alternative explanation could that the finding is a result of “healthy adherer” bias, in which people who take antihypertensive medication and follow a healthy lifestyle as advised would be more likely to take statins.

“The observational nature of our study does not allow us to determine the extent to which associations are causal,” the authors say.

Dr. Gaist also noted that an important caveat in this study is that they focused on individuals who had had a first ICH.

“This data does not inform us about those who have already had an ICH and are taking statins. But we are planning to look at this in our next study,” he said.

The study was funded by the Novo Nordisk Foundation. Dr. Gaist has received speaker honorarium from Bristol-Myers Squibb and Pfizer unrelated to this work.

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

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

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

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

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

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

A new meta-analysis of 884 studies evaluating 27 different types of antioxidant supplements has suggested that some of these micronutrients – including omega-3 fatty acids, folic acid, and coenzyme Q10 – may produce significant cardiovascular benefits.

Other antioxidant supplements that showed some evidence of reducing cardiovascular risk were omega-6 fatty acids, L-arginine, L-citrulline, magnesium, zinc, alpha-lipoic acid, melatonin, catechin, curcumin, flavanol, genistein, and quercetin.

No effect was seen with vitamin C, vitamin D, vitamin E, or selenium, and beta-carotene supplementation was linked to an increase in all-cause mortality in the analysis.

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

“Our systematic assessment and quantification of multiple differential effects of a wide variety of micronutrients and phytochemicals on cardiometabolic health indicate that an optimal nutritional strategy to promote cardiometabolic health will likely involve personalized combinations of these nutrients,” the authors, led by Peng An, PhD, China Agricultural University, Beijing, conclude.

“Identifying the optimal mixture of micronutrients is important, as not all are beneficial, and some may even have harmful effects,” senior author Simin Liu, MD, professor of epidemiology and medicine at Brown University, Providence, R.I., said in an American College of Cardiology press release.

“The micronutrients identified require further validation in large, high-quality interventional trials to establish clinical efficacy to determine their long-term balance of risks and benefits,” the authors add.
 

Experts cautious

Experts in the field of cardiovascular risk and preventative medicine have urged caution in interpreting these results.

JoAnn Manson, MD, chief of the division of preventive medicine at Brigham and Women’s Hospital, Boston, told this news organization that she has concerns that some of the results in the meta-analysis may be inflated by publication bias and some are chance findings that haven’t been well replicated.

“Although this meta-analysis of micronutrients and cardiometabolic health was based on randomized clinical trials, the quality of randomized trials on this subject varies widely,” she noted.

“The study is informative, but the conclusions are only as good as the quality of the evidence. Some of the trials are limited by short duration, and included trials have a wide range of quality, dosing, inclusion criteria, imperfect blinding, and few of them focus on hard clinical events,” Dr. Manson said. “Also, with trials of this nature, the potential for publication bias warrants consideration, because many of the smaller trials with unfavorable or neutral results may remain unpublished or not even be submitted for publication.”   

However, she added, “despite these limitations, this is an important contribution to the literature on micronutrients and health – and goes a long way in separating the wheat from the chaff.”

Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic, was more critical of the meta-analysis.

“This study does not make sense. Some of the ‘micronutrients’ in this meta-analysis have undergone thorough testing in large randomized clinical trials that showed different results. I am skeptical whether any of the purported benefits of these supplements would be confirmed in a high-quality randomized controlled trial,” he said.

Dr. Nissen added that many of the included studies are low in quality. “I must quote [renowned cardiologist, Dr.] Franz Messerli: ‘A meta-analysis is like making bouillabaisse. ... One rotten fish can spoil the broth.’ This type of analysis does not override high-quality large, randomized trials.”

In the JACC paper, the study investigators note that the American Heart Association now recommends dietary patterns, including the Mediterranean diet and DASH (the Dietary Approach to Stop Hypertension), as preventive or treatment approaches for cardiovascular disease. A common feature of these dietary patterns is that they are low in saturated fat and sodium and rich in micronutrients such as phytochemicals, unsaturated fatty acids, antioxidant vitamins, and minerals.

“To personalize cardiometabolic preventive and therapeutic dietary practices, it is of critical importance to have a comprehensive and in-depth understanding of the balance of benefits and risks associated with constituent micronutrients in diverse dietary patterns,” they note.

They therefore conducted the current systematic review and meta-analyses of all available randomized controlled trials investigating the effect of micronutrients with antioxidant properties on cardiovascular risk factors and events in diverse populations.

The meta-analysis included a total of 884 randomized trials evaluating 27 types of micronutrients among 883,627 participants.

Results showed that supplementation with n-3 fatty acids, n-6 fatty acids, L-arginine, L-citrulline, folic acid, magnesium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin, catechin, curcumin, flavanol, genistein, and quercetin had “moderate-to high-quality evidence” for reducing cardiovascular risk factors.

Specifically, n-3 fatty acid supplementation was linked to reduced rates of cardiovascular mortality (relative risk, 0.93), myocardial infarction (RR, 0.85), and coronary heart disease events (RR, 0.86). Folic acid supplementation was linked to a decreased stroke risk (RR, 0.84) and coenzyme Q10 was associated with a lower rate of all-cause mortality (RR, 0.68).

“The current study represents the first attempt in providing a comprehensive and most up-to-date evidence map that systematically assessed the quality and quantity of all randomized trials linking the effects of a wide variety of micronutrients on cardiovascular risk factors,” the authors say.

“The comprehensive evidence map presented here highlights the importance of micronutrient diversity and the balance of benefits and risks in the design of whole food–based dietary patterns to promote cardiometabolic health, which may require cultural adaptations to apply globally,” they conclude.

Commenting on some of the specific beneficial findings, Dr. Manson said: “I do believe that the marine omega-3s confer heart benefits, but results are not consistent and vary by dose and formulation.”

However, she pointed out that, regarding folic acid, a previous meta-analysis including eight large randomized trials in more than 37,000 participants found no reduction in coronary events, stroke, or major cardiovascular events with folic acid supplementation, compared with placebo, “so the reported stroke benefit would need further confirmation.”

In an accompanying editorial, Juan Gormaz, PhD, University of Chile, and Rodrigo Carrasco, MD, Chilean Society of Cardiology and Cardiovascular Surgery, both in Santiago, state: “Given that the compounds with more pleiotropic properties produced the better outcomes, the antioxidant paradigm on cardiovascular prevention can be challenged. For example, inasmuch as n-3 fatty acids have antiplatelet and anti-inflammatory properties, they are too complex to enable attribution of the observed benefits solely to their antioxidant capacity.”

The editorialists note that from a research point of view, “although the current information opens interesting perspectives for future consolidation of some antioxidants in preventive cardiology, there is still a long way to go in terms of generating evidence.”

They add that the challenge now for some compounds is to begin establishing consensus in definitions of dose and combinations, as well as continue strengthening the evidence of effectiveness.

“Regarding routine clinical practice, these results begin to open spaces for the integration of new tools into the therapeutic arsenal aimed at cardiovascular prevention in selected populations, which could be easily accessible and, with specific exceptions, would present a low frequency of adverse effects,” they conclude.

This work was partly supported by the United States’ Fulbright Program and by the Beijing Advanced Innovation Center for Food Nutrition and Human Health, the National Natural Science Foundation of China, the Chinese Universities Scientific Fund, and the Beijing Municipal Natural Science Foundation.

Dr. Liu has received honoraria for scientific presentations or reviews at Johns Hopkins University, Fred Hutchinson Cancer Center, Harvard University, University of Buffalo, Guangdong General Hospital, Fuwai Hospital, Chinese Academy of Medical Sciences, and the National Institutes of Health; he is a member of the Data Safety and Monitoring Board for several trials, including the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial sponsored by Novo Nordisk and a trial of pulmonary hypertension in diabetes patients sponsored by Massachusetts General Hospital; he has received royalties from UpToDate and has received an honorarium from the American Society for Nutrition for his duties as Associate Editor. Co-author Jeffrey Mechanick, MD, has received honoraria from Abbott Nutrition for lectures and serves on the advisory boards of Aveta.Life, L-Nutra, and Twin Health. The other authors report no relevant financial relationships.

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

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

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

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

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

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

Many more people are at risk for early cardiovascular events because of raised lipoprotein(a) levels than from having familial hypercholesterolemia (FH), a new study suggests.

The Danish study set out to try and establish a level of Lp(a) that would be associated with a cardiovascular risk similar to that seen with FH. As there are many different definitions of FH, results showed a large range of Lp(a) values that corresponded to risk levels of the different FH definitions.

However, if considering one of the broadest FH definitions (from MEDPED – Make Early Diagnoses, Prevent Early Deaths), which is the one most commonly used in the United States, results showed that the level of cardiovascular risk in patients with this definition of FH is similar to that associated with Lp(a) levels of around 70 mg/dL (0.7 g/L).

“While FH is fairly unusual, occurring in less than 1% of the population, levels of Lp(a) of 70 mg/dL or above are much more common, occurring in around 10% of the White population,” Børge Nordestgaard, MD, Copenhagen University Hospital, said in an interview. Around 20% of the Black population have such high levels, while levels in Hispanics are in between.

“Our results suggest that there will be many more individuals at risk of premature MI or cardiovascular death because of raised Lp(a) levels than because of FH,” added Dr. Nordestgaard, the senior author of the current study.

Dr. Nordestgaard explained that FH is well established to be a serious condition. “We consider FH to be the genetic disease that causes the most cases of early heart disease and early death worldwide.”

“But we know now that raised levels of Lp(a), which is also genetically determined, can also lead to an increased risk of cardiovascular events relatively early in life, and when you look into the numbers, it seems like high levels of Lp(a) could be more common than FH. We wanted to try and find the levels of Lp(a) that corresponded to similar cardiovascular risk as FH.”

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

The authors note that the 2019 joint European Society of Cardiology and European Atherosclerosis Society guidelines suggested that an Lp(a) level greater than 180 mg/dL (0.8 g/L) may confer a lifetime risk for heart disease equivalent to the risk associated with heterozygous FH, but they point out that this value was speculative and not based on a direct comparison of risk associated with the two conditions in the same population.

For their study, Dr. Nordestgaard and colleagues analyzed information from a large database of the Danish population, the Copenhagen General Population Study, including 69,644 individuals for whom data on FH and Lp(a) levels were available. As these conditions are genetically determined, and the study held records on individuals going back several decades, the researchers were able to analyze event rates over a median follow up time of 42 years. During this time, there were 4,166 cases of myocardial infarction and 11,464 cases of atherosclerotic cardiovascular disease (ASCVD).

Results showed that Lp(a) levels associated with MI risk equivalent to that of clinical FH ranged from 67 to 402 mg/dL depending on the definition used for FH. The Lp(a) level corresponding to the MI risk of genetically determined FH was 180 mg/dL.

In terms of risk of ASCVD events, the levels of Lp(a) corresponding to the risk associated with clinical FH ranged from 130 to 391 mg/dL, and the Lp(a) level corresponding to the ASCVD risk of genetically determined FH was 175 mg/dL.

“All these different definitions of FH may cause some confusion, but basically we are saying that if an individual is found to have an Lp(a) above 70 mg/dL, then they have a similar level of cardiovascular risk as that associated with the broadest definition of FH, and they should be taken as seriously as a patient diagnosed with FH,” Dr. Nordestgaard said.

He estimated that these individuals have approximately a doubling of cardiovascular risk, compared with the general population, and risk increases further with rising Lp(a) levels.

The researchers also found that if an individual has both FH and raised Lp(a) they are at very high risk, as these two conditions are independent of each other.

Although a specific treatment for lowering Lp(a) levels is not yet available, Dr. Nordestgaard stresses that it is still worth identifying individuals with raised Lp(a) as efforts can be made to address other cardiovascular risk factors.

“We know raised Lp(a) increases cardiovascular risk, but there are also many other factors that likewise increase this risk, and they are all additive. So, it is very important that individuals with raised Lp(a) levels address these other risk factors,” he said. “These include stopping smoking, being at healthy weight, exercising regularly, eating a heart-healthy diet, and aggressive treatment of raised LDL, hypertension, and diabetes. All these things will lower their overall risk of cardiovascular disease.”

And there is the promise of new drugs to lower Lp(a) on the horizon, with several such products now in clinical development.

Dr. Nordestgaard also points out that as Lp(a) is genetically determined, cascade screening of close relatives of the individual with raised Lp(a) should also take place to detect others who may be at risk.

Although a level of Lp(a) of around 70 mg/dL confers similar cardiovascular risk than some definitions of FH, Dr. Nordestgaard says lower levels than this should also be a signal for concern. 

“We usually say Lp(a) levels of 50 mg/dL are when we need to start to take this seriously. And it’s estimated that about 20% of the White population will have levels of 50 mg/dL or over and even more in the Black population,” he added. 
 

‘Screen for both conditions’

In an accompanying editorial, Pamela Morris, MD, Medical University of South Carolina, Charleston; Jagat Narula, MD, Icahn School of Medicine, New York; and Sotirios Tsimikas, MD, University of California, San Diego, say “the weight of evidence strongly supports that both genetic lipid disorders, elevated Lp(a) levels and FH, are causally associated with an increased risk of premature ASCVD and should be carefully considered in risk assessment and management for ASCVD risk reduction.”

Catherine Hackett/MDedge News

Dr. Morris told this news organization that the current study found a very large range of Lp(a) levels that conferred a similar cardiovascular risk to FH, because of the many different definitions of FH in use.

“But this should not take away the importance of screening for raised Lp(a) levels,” she stressed.  

“We know that increased Lp(a) levels signal a high risk of cardiovascular disease. A diagnosis of FH is also a high-risk condition,” she said. “Both are important, and we need to screen for both, but it is difficult to directly compare the two conditions because the different definitions of FH get in the way.”

Dr. Morris agrees with Dr. Nordestgaard that raised levels of Lp(a) may actually be more important for the population risk of cardiovascular disease than FH, as the prevalence of increased Lp(a) levels is higher.

“Because raised Lp(a) levels are more prevalent than confirmed FH, the risk to the population is greater,” she said.  

Dr. Morris points out that cardiovascular risk starts to increase at Lp(a) levels of 30 mg/dL (75 nmol/L).

The editorialists recommend that “in addition to performing a lipid panel periodically according to evidence-based guidelines, measurement of Lp(a) levels should also be performed at least once in an individual’s lifetime for ASCVD risk assessment.”

They conclude that “it is vital to continue to raise awareness among clinicians and patients of these high-risk genetic lipid disorders. Our understanding of both disorders is rapidly expanding, and promising novel therapeutics may offer hope for prevention of cardiovascular disease in patients with elevated Lp(a) levels in the future.”

This work was supported by Copenhagen University Hospital – Herlev Gentofte, Denmark, and the Danish Beckett-Foundation. The Copenhagen General Population Study is supported by the Copenhagen County Foundation and Copenhagen University Hospital – Herlev Gentofte. Dr. Nordestgaard has been a consultant and a speaker for AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

A new U.S. randomized trial has failed to show benefit of a 35-day course of oral anticoagulation with rivaroxaban for the prevention of thrombotic events in outpatients with symptomatic COVID-19.

The PREVENT-HD trial was presented at the American Heart Association scientific sessions by Gregory Piazza, MD, Brigham and Women’s Hospital, Boston.

“With the caveat that the trial was underpowered to provide a definitive conclusion, these data do not support routine antithrombotic prophylaxis in nonhospitalized patients with symptomatic COVID-19,” Dr. Piazza concluded.

PREVENT-HD is the largest randomized study to look at anticoagulation in nonhospitalized COVID-19 patients and joins a long list of smaller trials that have also shown no benefit with this approach.

However, anticoagulation is recommended in patients who are hospitalized with COVID-19.

Dr. Piazza noted that the issue of anticoagulation in COVID-19 has focused mainly on hospitalized patients, but most COVID-19 cases are treated as outpatients, who are also suspected to be at risk for venous and arterial thrombotic events, especially if they have additional risk factors. Histopathological evidence also suggests that at least part of the deterioration in lung function leading to hospitalization may be attributable to in situ pulmonary artery thrombosis.

The PREVENT-HD trial explored the question of whether early initiation of thromboprophylaxis dosing of rivaroxaban in higher-risk outpatients with COVID-19 may lower the incidence of venous and arterial thrombotic events, reduce in situ pulmonary thrombosis and the worsening of pulmonary function that may lead to hospitalization, and reduce all-cause mortality.

The trial included 1,284 outpatients with a positive test for COVID-19 and who were within 14 days of symptom onset. They also had to have at least one of the following additional risk factors: age over 60 years; prior history of venous thromboembolism (VTE), thrombophilia, coronary artery disease, peripheral artery disease, cardiovascular disease or ischemic stroke, cancer, diabetes, heart failure, obesity (body mass index ≥ 35 kg/m²) or D-dimer > upper limit of normal. Around 35% of the study population had two or more of these risk factors.

Patients were randomized to rivaroxaban 10 mg daily for 35 days or placebo.

The primary efficacy endpoint was time to first occurrence of a composite of symptomatic VTE, myocardial infarction, ischemic stroke, acute limb ischemia, non–central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality up to day 35.

The primary safety endpoint was time to first occurrence of International Society on Thrombosis and Hemostasis (ISTH) critical-site and fatal bleeding.

A modified intention-to-treat analysis (all participants taking at least one dose of study intervention) was also planned.

The trial was stopped early in April this year because of a lower than expected event incidence (3.2%), compared with the planned rate (8.5%), giving a very low likelihood of being able to achieve the required number of events.

Dr. Piazza said reasons contributing to the low event rate included a falling COVID-19 death and hospitalization rate nationwide, and increased use of effective vaccines.

Results of the main intention-to-treat analysis (in 1,284 patients) showed no significant difference in the primary efficacy composite endpoint, which occurred in 3.4% of the rivaroxaban group versus 3.0% of the placebo group.

In the modified intention-to-treat analysis (which included 1,197 patients who actually took at least one dose of the study medication) there was shift in the directionality of the point estimate (rivaroxaban 2.0% vs. placebo 2.7%), which Dr. Piazza said was related to a higher number of patients hospitalized before receiving study drug in the rivaroxaban group. However, the difference was still nonsignificant. 

The first major secondary outcome of symptomatic VTE, arterial thrombotic events, and all-cause mortality occurred in 0.3% of rivaroxaban patients versus 1.1% of placebo patients, but this difference did not reach statistical significance.

However, a post hoc exploratory analysis did show a significant reduction in the outcome of symptomatic VTE and arterial thrombotic events. 

In terms of safety, there were no fatal critical-site bleeding events, and there was no difference in ISTH major bleeding, which occurred in one patient in the rivaroxaban group versus no patients in the placebo group.

There was, however, a significant increase in nonmajor clinically relevant bleeding with rivaroxaban, which occurred in nine patients (1.5%) versus one patient (0.2%) in the placebo group.

Trivial bleeding was also increased in the rivaroxaban group, occurring in 17 patients (2.8%) versus 5 patients (0.8%) in the placebo group.

Discussant for the study, Renato Lopes, MD, Duke University Medical Center, Durham, N.C., noted that the relationship between COVID-19 and thrombosis has been an important issue since the beginning of the pandemic, with many proposed mechanisms to explain the COVID-19–associated coagulopathy, which is a major cause of death and disability.

While observational data at the beginning of the pandemic suggested patients with COVID-19 might benefit from anticoagulation, looking at all the different randomized trials that have tested anticoagulation in COVID-19 outpatients, there is no treatment effect on the various different primary outcomes in those studies and also no effect on all-cause mortality, Dr. Lopes said. 

He pointed out that PREVENT-HD was stopped prematurely with only about one-third of the planned number of patients enrolled, “just like every other outpatient COVID-19 trial.”

He also drew attention to the low rates of vaccination in the trial population, which does not reflect the current vaccination rate in the United States, and said the different direction of the results between the main intention-to-treat and modified intention-to-treat analyses deserve further investigation.

However, Dr. Lopes concluded, “The results of this trial, in line with the body of evidence in this field, do not support the routine use of any antithrombotic therapy for outpatients with COVID-19.”

The PREVENT-HD trial was sponsored by Janssen. Dr. Piazza has reported receiving research support from Bristol-Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific, and consulting fees from Bristol-Myers Squibb/Pfizer Alliance, Boston Scientific, Janssen, NAMSA, Prairie Education and Research Cooperative, Boston Clinical Research Institute, and Amgen.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

Use of a combination antihypertensive product containing quarter doses of four different drugs could be an effective strategy to get patients to target blood pressures in one step, a new study suggests. 

The study, QUARTET-USA, showed a reduction in BP of almost 5 mm Hg more than the comparator of one antihypertensive agent at standard dose over the 12-week follow-up period in patients with mild to moderate hypertension.

The QUARTET-USA study was presented at the American Heart Association scientific sessions by Mark Huffman, MD, professor of medicine at Washington University in St. Louis. 

It builds on a previous trial, QUARTET, conducted in Australia, which first showed benefits with this approach.

In the new U.S. study, which was considerably smaller than the Australian trial, the four-drug combination, including candesartan, amlodipine, indapamide, and bisoprolol, led to a –4.8/–4.9 mm Hg greater reduction in BP from baseline to 12 weeks, compared with standard-dose candesartan monotherapy.

Differences in systolic BP were not statistically significant, which is likely because of limited power related to the sample size, Dr. Huffman noted.

Adverse events were more common in the four-drug intervention group, but the rate of discontinuation was higher in the comparator group. No severe adverse events were deemed related to the study drug.

“The direction and magnitude of [the] blood pressure–lowering effect were similar between the previous Australian study and this American study, despite different populations with lower baseline blood pressure in the current study, thus strengthening the case for this new approach,” Dr. Huffman concluded.

“The two studies together show that the approach of using four drugs in quarter doses is more effective in lowering blood pressure than a single standard dose antihypertensive agent and has an acceptable safely profile,” he said in an interview.

He said the four-drug combination could be an effective way of getting patients to target without multiple appointments.

“If you think about how many visits to the doctor’s office it takes to get patients to goal blood pressures, this combination gets patients down to new guideline target levels in one step, whereas in the SPRINT trial it took three or more visits to get down to these levels. And in practice we lose people – they don’t come back,” he said.

Dr. Huffman explained that the rationale for the study was the persistently low hypertension control rate, which demonstrates the need for a new approach.

The previous Australian QUARTET study suggested that ultra–low-dose combination therapy has a favorable balance between blood pressure–lowering effect, tolerability, and adherence.

That study, conducted in 591 patients and reported in 2021, demonstrated a greater BP-lowering effect with a four-drug combination at quarter doses (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) at 12 weeks, compared with irbesartan 150 mg daily. Systolic BP was reduced by more than 6.9 mm Hg and diastolic BP by 5.8 mm Hg than full-dose irbesartan alone, both significant differences.

The current study, QUARTET-USA, aimed to see if a similar strategy could produce comparable results in a U.S. population.

The U.S. study included 62 patients from the Access Community Health Network, Chicago, who were either treatment naive with BPs above 140/90 mm Hg, or already taking antihypertensive monotherapy with BPs above 130/85 mm Hg.

The mean systolic BP at baseline was 138 mm Hg and the mean diastolic pressure was 84 mm Hg.

Study participants were mainly from ethnic minorities (90% Hispanic or Black) and over half were from low-income households (annual household income less than $25,000).

They were randomly assigned to daily administration of a four-drug combination at quarter doses (candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, bisoprolol 2.5 mg) or a full dose of candesartan 8 mg (the comparator arm).

Amlodipine 5 mg daily could be added on to treatment if BP remained above 130/80 mm Hg at 6 weeks. This occurred in 18% of the study group versus 53% of the comparator group.

Results showed that at 12 weeks the adjusted mean change in systolic BP weeks was –4.8 mm Hg (95% CI,–10.7 to 1.2), and the adjusted mean change in diastolic BP was –4.9 mm Hg (95% CI, –8.6 to –1.1) in the four-drug combination group, compared with the comparator arm.

Average BPs at the end of 12-week study period were 121 mm Hg systolic and 73 mm Hg diastolic in the four-drug intervention group, compared with 124 mm Hg systolic and 77 mm Hg diastolic in the comparator group.

Any adverse events that were possibly related to drug therapy occurred in 25% of the intervention group versus 10% of the comparator group. But adverse events leading to discontinuation occurred in 6.3% of the study group versus 26.7% of patients in the comparator arm.

“New approaches are needed to achieve lower blood pressure targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases. QUARTET-USA was the first trial of a four-drug, ultra–low-dose, blood pressure–lowering combination therapy in the U.S.,” Dr. Huffman said.

“We showed reductions in blood pressure similar in magnitude to those in the Australian study. It is useful to know that the direction of the effect is similar across varied populations. Now that we have that signal of efficacy and tolerability, we can move to actually getting it into the hands of patients and providers,” he added.

Noting that further studies will be required to attain marketing authorization, Dr. Huffman suggested that a pharmaceutical company would need to complete that process.

“These are promising results for companies who may be interested in partnering,” he said.

‘A more efficient approach’ 

LaPrincess C. Brewer, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minn., and discussant of the study, said the QUARTET-USA study suggests the four-drug, low-dose combination shows promise in lowering BP, compared with the standard dose, and while the reduction in systolic BP was not quite significant, it was clinically meaningful.

“Most U.S. adults with hypertension do not have it under control. This is due to unfavorable social and structural determinants of health which limit adherence to antihypertensive medication,” Dr. Brewer noted.  

From a patient point of view, the multiple visits needed to attain goals are a burden and there is also the issue of clinical inertia and lack of medication intensification by clinicians, she commented. 

“Of patients with uncontrolled hypertension, 40% are taking just one antihypertensive medication, so up-front, low-dose combination therapy is likely a more efficient approach,” she said.

“This study builds the evidence base for the need for tailored interventions that address the social determinants of health and the intentional prioritization of diverse population in clinical trials,” Dr. Brewer concluded.

QUARTET was an investigator-initiated study, Dr. Huffman reported a pending patent for a heart failure polypill. The George Institute for Global Health, Sydney, Australia, where Huffman has a secondary appointment, has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy. Dr. Brewer reported research support from the National Institutes of Health, Centers for Disease Control and Prevention, American Heart Association, and Bristol-Meyers Squibb Foundation.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

A new Japanese study of highly purified eicosapentaenoic acid (EPA; icosapent ethyl) has suggested a possible benefit in reducing adverse cardiovascular events in patients with chronic coronary artery disease taking statins.

The open-label randomized RESPECT-EPA study showed a reduction of borderline statistical significance in its primary endpoint of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina, and coronary revascularization in patients allocated to the EPA product at a dosage of 1,800 mg/day.

The results were presented at the American Heart Association scientific sessions by Hiroyuki Daida, MD, Juntendo University Graduate School of Medicine, Japan. 

However, the trial has several limitations, including a high number of patient withdrawals or protocol deviations, and as such, its conclusions are uncertain.  

Regardless, it has inevitably added to the debate on the cardiovascular benefits of EPA, which were shown in the REDUCE-IT trial. However, that trial has been dogged with controversy because of concerns that the mineral oil placebo used may have had an adverse effect.

Commenting on the new RESPECT-EPA trial for this article, lead investigator of the REDUCE-IT trial, Deepak Bhatt, MD, said the results were consistent with REDUCE-IT and another previous Japanese trial, the Japan EPA Lipid Intervention Study (JELIS), and added to the evidence supporting cardiovascular benefits of EPA.

“In isolation, this study may not be viewed as showing conclusive benefits, but looking at the totality of the data from this trial and from the field more widely, this together shows a convincing cardiovascular benefit with EPA,” Dr. Bhatt said. “We now have 3 randomized controlled trials all showing benefits of highly purified EPA in reducing cardiovascular events.”

However, long-time critic of the REDUCE-IT trial, Steve Nissen, MD, Cleveland Clinic, was not at all impressed with the RESPECT-EPA trial and does not believe it should be used to support the EPA data from REDUCE-IT. 

“The many limitations of the RESPECT-EPA trial make it uninterpretable. It just doesn’t meet contemporary standards for clinical trials,” Dr. Nissen said in an interview. “I don’t think it sheds any light at all on the debate over the efficacy of EPA in cardiovascular disease.”

Dr. Nissen was the lead investigator of another largescale trial, STRENGTH, which showed no benefit of a different high dose omega-3 fatty acid product including a combination of EPA and docosahexaenoic acid (DHA).  

In his AHA presentation on the RESPECT-EPA study, Dr. Daida explained as background that in 2005, JELIS first demonstrated a beneficial effect of highly purified EPA on cardiovascular outcomes in patients with and without coronary artery disease. 

Recently, optimal medical therapy, particularly with high-intensity statins, has become the gold standard of care for patients with coronary artery disease, but they are still at substantially high residual risk, he noted.

Despite of the evidence provided by JELIS, the conflicting results in recent omega-3 fatty acid trials (REDUCE-IT and STRENGTH) have led to an intense controversy regarding the relevance of EPA intervention on top of the latest optimal medical therapy, Dr. Daida said.

The current study – Randomized trial for Evaluating the Secondary Prevention Efficacy of Combination Therapy Statin and EPA (RESPECT-EPA) – was conducted to determine the effect of highly purified EPA on cardiovascular events in Japanese patients with chronic coronary artery disease and a low EPA/arachidonic acid (AA) ratio (< 0.4), who were already receiving statins.

They were randomly assigned to highly purified EPA (icosapent ethyl, 1,800 mg/day) plus statin therapy or to statin therapy alone.

The enrollment period started in 2013 and continued for 4 years. Patients were followed for a further 4 years from the end of the enrollment period.

The trial included 2,506 patients, 1,249 assigned to the EPA group and 1,257 to the control group. In both groups there were a high number of early withdrawals or protocol deviations (647 in the EPA group and 350 in the control group).

The analysis was conducted on 1,225 patients in the EPA group and 1,235 patients in the control group, although at 6 years’ follow-up there were fewer than 400 patients in each arm.  

Baseline characteristics showed median low-density lipoprotein (LDL) cholesterol levels of 80 mg/dL, EPA levels of 45 mcg/mL, and triglyceride levels of 120 mg/dL.

The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, unstable angina, and coronary revascularization showed a borderline significant reduction in the EPA group at 6 years since the start of randomization (10.9% vs. 14.9%; hazard ratio, 0.785; P = .0547).

The secondary endpoint, a composite of sudden cardiac death, MI, unstable angina, and coronary revascularization, showed a significant reduction in the EPA group (8.0% vs. 11.3%; HR, 0.734; P = .0306).

In terms of adverse events, there was an increase in gastrointestinal disorders (3.4% vs. 1.2%) and new-onset atrial fibrillation (3.1% vs. 1.6%) in the EPA group.

In a post hoc analysis, which excluded patients with an increase of more than 30 mcg/mL in the control group (182 patients) and those with an increase of less than 30 mcg/mL in the EPA group (259 patients), the primary endpoint showed a significant reduction the EPA group (HR, 0.725; P = .0202).

Dr. Daida noted that limitations of the study included a lower than expected event rate (suggesting that the study may be underpowered), an open-label design, and the fact that baseline levels of EPA in this Japanese population would be higher than those in Western countries.
 

‘Massive loss’ of patients

Critiquing the study, Dr. Nissen highlighted the large dropout and protocol violation rate.

“There was a massive loss of patients over the 6- to 8-year follow-up, and the Kaplan-Meier curves didn’t start to diverge until after 4 years, by which time many patients had dropped out. It would have been a very selective population that lasted 6 years in the study. Patients that drop out are different to those that stay in, so they are cherry-picking the patients that persist in the trial. There is enormous bias here,” he commented. 

“Another weakness is the open-label design. Everyone knew who is getting what. Blinding is important in a study. And there was no control treatment in this trial,” he noted.

The researchers also selected patients with low EPA levels at baseline, Dr. Nissen added. “That is completely different hypothesis to what was tested in the REDUCE-IT and STRENGTH trials. And even with all these problems, the results are still statistically insignificant.”  

On the post hoc subgroup analysis showing a significant benefit, Dr. Nissen said, “they compared a subgroup in the active treatment arm who had large increases in EPA to a subgroup of control patients who had the smallest increase in EPA. That would be like comparing patients who had the largest reductions in LDL in a statin trial to those in the control arm who had no reductions or increases in LDL. That’s scientifically totally inappropriate.”
 

Supportive data

But Dr. Bhatt argues that the RESPECT-EPA trial supports the two previous trials showing benefits of EPA.

“Some may quibble with the P value, but to me this study has shown clear results, with obvious separation of the Kaplan-Meier curves,” he said.  

“It is an investigator-initiated study, which is good in principle but has some of the usual caveats of such a study in that – probably as a consequence of budget constraints – it has an open-label design and is underpowered. But as they did not use a placebo and still showed a benefit of EPA, that helps resolve the issue of the placebo used in REDUCE-IT for those who were concerned about it,” Dr. Bhatt noted.  

He pointed out that the 1,800-mg dose of EPA is the same dose used in the JELIS trial and is the dose used in Japan. The REDUCE-IT trial used a higher dose (4 g), but in general, Japanese people have higher levels of EPA than Western populations, he explained.  

“While this trial included patients with lower levels of EPA, what is considered low in Japan is much higher than average American levels,” he added.
 

Magnitude of benefit uncertain?

Discussant of the study at the Late Breaking Clinical Trials session, Pam R. Taub, MD, professor of medicine at the University of California, San Diego School of Medicine, said, “Despite being underpowered with a sample size of 2,460, RESPECT-EPA shows benefit in decreasing composite coronary events.”

“There is benefit with EPA, but the magnitude of benefit is uncertain,” she stated.

Dr. Taub pointed out that there is a signal across studies for new-onset atrial fibrillation, but the absolute increase is “rather small.”

She noted that more mechanistic and clinical data are needed to hone in on which patients will derive the most benefit, such as those with elevated high-sensitivity C-reactive protein or highest change in EPA levels. But she concluded that in clinical practice, physicians could consider addition of EPA for reduction of residual risk in secondary prevention patients.

The RESPECT-EPA study was supported by the Japan Heart Foundation. Dr. Daida reports peakers’ bureau/honorarium fees from Novartis Pharma, Bayer Yakuhin, Sanofi, Kowa Company, Taisho Pharmaceutical, Abbott Medical Japan, Otsuka Pharmaceutical, Amgen, MSD, Daiichi Sankyo, Pfizer Japan, FUKUDA DENSHI, Tsumura, and TOA EIYO and research funding from Philips Japan, FUJIFILM Holdings, Asahi Kasei, Inter Reha, TOHO HOLDINGS, GLORY, BMS, Abbott Japan, and Boehringer Ingelheim Japan.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

There was no difference in major cardiovascular outcomes with the use of two different diuretics – chlorthalidone or hydrochlorothiazide – in the treatment of hypertension in a new large randomized real-world study.

The Diuretic Comparison Project (DCP), which was conducted in more than 13,500 U.S. veterans age 65 years or over, showed almost identical rates of the primary composite endpoint, including myocardial infarction (MI), stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization, after a median of 2.4 years of follow-up.

There was no difference in any of the individual endpoints or other secondary cardiovascular outcomes.

However, in the subgroup of patients who had a history of MI or stroke (who made up about 10% of the study population), there was a significant reduction in the primary endpoint with chlorthalidone, whereas those without a history of MI or stroke appeared to have an increased risk for primary outcome events while receiving chlorthalidone compared with those receiving hydrochlorothiazide.

The DCP trial was presented at the American Heart Association scientific sessions by Areef Ishani, MD, director of the Minneapolis Primary Care and Specialty Care Integrated Care Community and director of the Veterans Affairs (VA) Midwest Health Care Network.

Asked how to interpret the result for clinical practice, Dr. Ishani said, “I think we can now say that either of these two drugs is appropriate to use for the treatment of hypertension.”

But he added that the decision on what to do with the subgroup of patients with previous MI or stroke was more “challenging.”

“We saw a highly significant benefit in this subgroup, but this was in the context of an overall negative trial,” he noted. “I think this is a discussion with the patients on how they want to hedge their bets. Because these two drugs are so similar, if they wanted to take one or the other because of this subgroup result I think that is a conversation to have, but I think we now need to conduct another trial specifically in this subgroup of patients to see if chlorthalidone really is of benefit in that group.”

Dr. Ishani explained that both chlorthalidone and hydrochlorothiazide have been around for more than 50 years and are considered first-line treatments for hypertension. Early studies suggested better cardiovascular outcomes and 24-hour blood pressure control with chlorthalidone, but recent observational studies have not shown more benefit with chlorthalidone. These studies have suggested that chlorthalidone may be associated with an increase in adverse events, such as hypokalemia, acute kidney injury, and chronic kidney disease.
 

Pragmatic study

The DCP trial was conducted to try to definitively answer this question of whether chlorthalidone is superior to hydrochlorothiazide. The pragmatic study had a “point-of-care” design that allowed participants and health care professionals to know which medication was being prescribed and to administer the medication in a real-world setting.

“Patients can continue with their normal care with their usual care team because we integrated this trial into primary care clinics,” Dr. Ishani said. “We followed participant results using their electronic health record. This study was nonintrusive, cost-effective, and inexpensive. Plus, we were able to recruit a large rural population, which is unusual for large, randomized trials, where we usually rely on big academic medical centers.”

Using VA electronic medical records, the investigators recruited primary care physicians who identified patients older than age 65 years who were receiving hydrochlorothiazide (25 mg or 50 mg) for hypertension. These patients (97% of whom were male) were then randomly assigned to continue receiving hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone. Patients were followed through the electronic medical record as well as Medicare claims and the National Death Index.

Results after a median follow-up of 2.4 years showed no difference in blood pressure control between the two groups.

In terms of clinical events, the primary composite outcome of MI, stroke, noncancer death, hospitalization for acute heart failure, or urgent revascularization occurred in 10.4% of the chlorthalidone group and in 10.0% of the hydrochlorothiazide group (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.94-1.16; P = .4).

There was no difference in any individual components of the primary endpoint or the secondary outcomes of all-cause mortality, any revascularization, or erectile dysfunction.

In terms of adverse events, chlorthalidone was associated with an increase in hypokalemia (6% vs. 4.4%; HR, 1.38), but there was no difference in hospitalization for acute kidney injury.
 

Benefit in MI, stroke subgroup?

In the subgroup analysis, patients with a history of MI or stroke who were receiving chlorthalidone had a significant 27% reduction in the primary endpoint (HR, 0.73; 95% CI, 0.57-0.94). Conversely, patients without a history of MI or stroke appeared to do worse while taking chlorthalidone (HR, 1.12; 95% CI, 1.00-1.26).

“We were surprised by these results,” Dr. Ishani said. “We expected chlorthalidone to be more effective overall. However, learning about these differences in patients who have a history of cardiovascular disease may affect patient care. It’s best for people to talk with their health care clinicians about which of these medications is better for their individual needs.”

He added: “More research is needed to explore these results further because we don’t know how they may fit into treating the general population.”

Dr. Ishani noted that a limitations of this study was that most patients were receiving the low dose of chlorthalidone, and previous studies that suggested benefits with chlorthalidone used the higher dose.

“But the world has voted – we had 4,000 clinicians involved in this study, and the vast majority are using the low dose of hydrochlorothiazide. And this is a definitively negative study,” he said. “The world has also voted in that 10 times more patients were on hydrochlorothiazide than on chlorthalidone.”

Commenting on the study at an AHA press conference, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, pointed out that in all of the landmark National Institutes of Health hypertension trials, there was a signal for benefit with chlorthalidone compared with other antihypertensives.

Catherine Hackett/MDedge News

“We’ve always had this concept that chlorthalidone is better,” she said. “But this study shows no difference in major cardiovascular endpoints. There was more hypokalemia with chlorthalidone, but that’s recognizable as chlorthalidone is a more potent diuretic.”

Other limitations of the DCP trial are its open-label design, which could interject some bias; the enduring effects of hydrochlorothiazide – most of these patients were receiving this agent as background therapy; and inability to look at the effectiveness of decongestion of the agents in such a pragmatic study, Dr. Bozkurt noted.

She said she would like to see more analysis in the subgroup of patients with previous MI or stroke. “Does this result mean that chlorthalidone is better for sicker patients or is this result just due to chance?” she asked.

“While this study demonstrates equal effectiveness of these two diuretics in the targeted population, the question of subgroups of patients for which we use a more potent diuretic I think remains unanswered,” she concluded.

Designated discussant of the DCP trial at the late-breaking trial session, Daniel Levy, MD, director of the Framingham Heart Study at the National Heart, Lung, and Blood Institute, reminded attendees that chlorthalidone had shown impressive results in previous important hypertension studies including SHEP and ALLHAT.

He said the current DCP was a pragmatic study addressing a knowledge gap that “would never have been performed by industry.”

Dr. Levy concluded that the results showing no difference in outcomes between the two diuretics were “compelling,” although a few questions remain.

These include a possible bias toward hydrochlorothiazide – patients were selected who were already taking that drug and so would have already had a favorable response to it. In addition, because the trial was conducted in an older male population, he questioned whether the results could be generalized to women and younger patients.

The DCP study was funded by the VA Cooperative Studies Program. Dr. Ishani reported no disclosures.

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A study evaluating a new approach using a combination of two thrombolytics designed to reduce bleeding risk in patients with acute ischemic stroke has not shown any benefit on the primary outcome of all intracranial hemorrhage (ICH).

However, there were some encouraging findings including a trend towards a reduction in symptomatic ICH, researchers report, and the combination approach did not show any depletion of fibrinogen levels, which suggests a potential lower bleeding risk.

“Although the main results of this study are neutral, we are encouraged that the combination approach with a low dose of alteplase followed by the new mutant pro-urokinase product looked as effective as full-dose alteplase alone, and there were some promising signs signaling a potential lower bleeding risk,” senior investigator, Diederik Dippel, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization.  

The DUMAS study (Dual Thrombolytic Therapy With Mutant Pro-Urokinase and Low Dose Alteplase for Ischemic Stroke) was presented at the World Stroke Congress in Singapore by study coauthor Nadinda van der Ende, MD, also from Erasmus University Medical Center. 

She pointed out that thrombolysis with intravenous alteplase increases the likelihood of a good outcome in acute ischemic stroke but can cause symptomatic intracranial hemorrhage, which can be associated with death and major disability.

Mutant pro-urokinase is a new thrombolytic agent, in development by Thrombolytic Science, Cambridge, Mass., formed by changing one amino acid in pro-urokinase to make it more stable. It is more fibrin specific than alteplase and therefore believed to have a lower risk of intracranial hemorrhage.

Fibrin is formed as the last step in the clotting process, and the precursor of fibrin in the blood is fibrinogen, Dr. van der Ende noted. Alteplase depletes fibrinogen, contributing to its increased bleeding risk, but mutant pro-urokinase is not believed to affect fibrinogen.

“Mutant pro-urokinase does not bind to intact fibrin. It only binds to fibrin that has already been primed by alteplase,” she explained.

The hypothesis behind the current study is that giving a small dose of alteplase will break down fibrin in the clot enough to expose the binding sites for mutant pro-urokinase, which can then be given to continue to lyse the clot.  

As alteplase has a short half-life, it disappears quickly, and new fibrin is not affected. As mutant pro-urokinase can only lyse fibrin that is primed with alteplase, new hemostatic clots should stay intact. Animal studies have shown less bleeding from distant sites with this approach, Dr. van der Ende said.

The primary analysis of the phase 2 DUMAS study included 238 patients with mild ischemic stroke (median National Institutes of Health Stroke Scale [NIHSS] score 3) who met the standard criteria for IV alteplase.

They were randomized to alteplase alone at the regular dose of 0.9 mg/kg (max 90 mg) with a 10% bolus and the remaining given over 60 minutes; or to a combination of a 5-mg bolus of IV alteplase followed by mutant pro-urokinase at a dose of 40 mg given over 60 minutes.

The primary outcome was the rate of all intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging.  

This occurred in 14% of patients in the full-dose alteplase group vs. 13% of patients in the combined alteplase/mutant pro-urokinase group, a nonsignificant difference: adjusted odds ratio, 0.99 (95% confidence interval, 0.46-2.14).

Secondary outcomes showed no significant differences in NIHSS scores at 24 hours or 5-7 days; functional outcome as measured by a shift analysis of the Modified Rankin Scale (mRS); final infarct volume; or perfusion deficit.

However, blood fibrinogen levels were not depleted and significantly higher in the alteplase/mutant pro-urokinase group than in the full-dose alteplase alone group.

In terms of safety, symptomatic ICH occurred in three patients in the alteplase group (3%) and in none (0%) in the combined alteplase/mutant pro-urokinase group; death occurred in 4% vs. 2% patients respectively; and major extracranial hemorrhage occurred in 1% in both groups.

Dr. Van der Ende concluded that the study showed an overall low rate of ICH; a combination of alteplase and mutant pro-urokinase was not superior to alteplase alone in reducing ICH rates in this population of patients with minor stroke; and mutant pro-urokinase appeared to be safe and, unlike alteplase, did not show any reduction in fibrinogen levels.

“We think the lack of an effect on fibrinogen with this new combination of a small alteplase bolus followed by mutant pro-urokinase infusion is promising,” Dr. Dippel commented. “The fact that there was no symptomatic ICH with the combination treatment is also encouraging. Although the primary endpoint of this trial was neutral, we still believe this is a very interesting approach, with the potential for reduced bleeding, compared with alteplase alone, but we need larger numbers to see an effect on outcomes.”

Dr. Dippel also pointed out that the study included only patients with minor stroke who were not eligible for endovascular therapy, and these patients have a low risk of a poor outcome and a low bleeding risk. 

They are hoping to do another study in patients with more severe stroke, who have a higher bleeding risk and would have more to gain from this combination approach.

Because many patients with severe stroke now have immediate thrombectomy if they present to a comprehensive stroke center, a trial in severe stroke patients would have to be done in primary stroke centers, so if the patents are referred to thrombectomy, the thrombolytic would have a chance to work, Dr. Dippel added.

Commenting on the study for this news organization, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the World Stroke Congress scientific committee, said, “Alteplase is not fibrin specific, and also causes a degeneration of fibrinogen, which results in ‘fibrinogen depletion coagulopathy.’ It is assumed that 20%-40% of intracerebral bleeding after thrombolysis with alteplase is caused by this problem. DUMAS tests the combination of a substantially reduced alteplase [5 mg] dose plus mutant pro-urokinase to avoid this problem.”

The new thrombolysis protocol, however, did not result in a lower bleeding risk, compared to the comparator alteplase,” he added. “The main limitation of this study is that mainly patients with minor strokes were included. Patients with moderate and severe strokes, who have a substantial risk of bleeding, were not adequately addressed.”

The DUMAS trial was funded by an unrestricted grant from Thrombolytic Science, paid to the institution. Dr. Van der Ende and Dr. Dippel report no relevant disclosures.
 

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

A large randomized trial that was investigating intensive lowering of blood pressure in acute ischemic stroke patients who had undergone mechanical thrombectomy has been stopped early because of safety concerns.

“Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischemic stroke due to intracranial large-vessel occlusion,” the investigators conclude.

Results from the ENCHANTED2/MT trial were presented by Craig Anderson, MD, professor of neurology and epidemiology, University of New South Wales, Sydney, during the 14th World Stroke Congress (WSC) in Singapore.

The study was simultaneously published online in The Lancet.

“What our results have pretty convincingly shown is that in acute stroke patients who have undergone mechanical thrombectomy, lowering blood pressure down to a systolic of 120 mm Hg for 3 days is too low for too long. We shouldn’t go that far down,” Dr. Anderson said in an interview.

Dr. Anderson said the trial has provided an important message for clinical practice.

“This result is not what we expected, but it is a definitive result and gives us a lower safety margin for blood pressure in acute ischemic stroke patients. This, in itself, is a big step forward.”

He noted that the optimum blood pressure for these patients is not known.

“We need to do further trials to determine optimum blood pressure in these acute patients, but perhaps we should be aiming more towards 140 mm Hg,” he suggested.

“But this trial shows us that in patients who have had successful clot retrieval with endovascular treatment for acute ischemic stroke, careful blood pressure management is important to avoid levels becoming too low. We have to make sure we don’t overshoot down to 120 mm Hg or below.”

The chair of the WSC session at which the trial was presented, Jeyaraj Pandian, MD, head of neurology at Christian Medical College, Ludhiana, India, who is the current vice-president of the World Stroke Organization, said: “This is a very important result. It has major practical implications.”

As background, Dr. Anderson explained that elevated blood pressure is very common in patients who have an acute ischemic stroke, and the higher the blood pressure, the higher the chances of having a worse outcome.

“Theoretically, if we can control the blood pressure, we may be able to improve outcomes,” he said.

In 2019, the first ENCHANTED trial reported that controlling blood pressure by a moderate amount – to around 140 mm Hg, which is lower than currently recommended in the guidelines – was linked to a reduction in bleeding complications of thrombolysis and appeared safe, but it did not improve recovery, Dr. Anderson noted.

“This trial was done before mechanical thrombectomy became routinely adopted, and this procedure has now become the standard of care for large-vessel occlusion strokes, but we don’t know what we should do about blood pressure in these patients,” he added.

A smaller French trial has suggested lowering blood pressure to 130 mm Hg, rather than a more liberal 130-180 mm Hg, was safe after successful mechanical thrombectomy, but there was no effect on functional outcome.

“In stroke patients with a large-vessel occlusion, blood pressure is often elevated to very high levels. There are wide ranges of opinions on what to do about this – whether it should be lowered, and by how much,” Dr. Anderson said. “We conducted the current ENCHANTED2/MT trial to look at this issue.”

The trial randomly assigned patients who had undergone successful mechanical clot retrieval and reperfusion but whose blood pressure was still elevated to two groups. In one group, blood pressure was aggressively lowered to less than 120 mm Hg within 1 hour of reperfusion, and blood pressure was kept at this level for 3 days. In the other group, a more liberal approach was used: Blood pressure was kept at 140-180 mm Hg.

The primary endpoint was disability, as measured by the Modified Rankin Scale (mRS) score at 90 days.

The study was started in China with the intention of expanding recruitment internationally. The planned enrollment was more than 2,000 patients.

However, in March of 2022, after 821 patients had been enrolled, the data safety monitoring board (DSMB) recommended that recruitment into the trial be suspended because of a safety signal. All of the patients who had been recruited were from China.

These patients were followed to obtain the 3-month outcome results, after which the DSMB recommended that the trial be stopped because safety was still a problem.

Mean systolic blood pressure was 125 mm Hg at 1 hour and 121 mm Hg at 24 hours in the more intensive-treatment group; it was 143 mm Hg at 1 hour and 139 mm Hg at 24 hours in the less intensive-treatment group, giving an adjusted mean difference over 24 hours of 18 mm Hg.
 

Worse disability scores

Results showed that the patients who underwent the more intensive blood pressure lowering had more disability at 3-month follow-up, with worse scores on a shift analysis of the mRS than those in the less intensive group (common odds ratio, 1.37; 95% confidence interval, 1.07-1.76).

The unfavorable shift in mRS scores in the more intensive group was consistent in adjusted sensitivity analysis, and there was no significant heterogeneity in the treatment effect on the primary outcome across all prespecified subgroups.

The incidence of death or neurologic deterioration at 7 days was higher in the more intensive-treatment group than the less intensive-treatment group (common OR, 1.53), and a between-group difference emerged at 24 hours.

The incidence of death or disability (mRS scores, 3-6) at 90 days was higher among patients in the more intensive-treatment group than the less intensive-treatment group (53% vs. 39%; OR, 1.85; P = .0001).

Among those who survived, more patients in the more intensive-treatment group had major disability (mRS scores, 3-5) at 90 days than did patients in the less intensive-treatment group (43% vs. 28%; OR, 2.07; P = .0001).
 

No difference in ICH or severe hypotension episodes

The incidence of symptomatic intracranial hemorrhage, mortality, and serious adverse events did not significantly differ between the two groups. There were no significant differences in recurrent ischemic stroke events at 90 days, and no episodes of severe hypotension were reported as a serious adverse event.

“Our results show that intensive lowering of blood pressure appears to be associated with worsening physical disability. While there was no difference in mortality rates between the two groups, the lower blood pressure appeared to compromise the ability to recover from the stroke,” Dr. Anderson said.

On the possible mechanism of harm, he suggested that the intensive blood pressure reduction might be interfering with blood flow through the injured part of the brain and impeding the ability to recover from the clot removal procedure.
 

What levels should be aimed for?

Dr. Anderson stressed that it was important to have conducted this trial.

“Current guidelines recommend very conservative level of blood pressure in acute ischemic stroke patients – to below 180 mm Hg. But no lower limit is recommended.

“Most clinicians aim for about the 140 mm Hg mark, but there is a large variation in opinion on what to do,” he said. “Some doctors treat aggressively, believing that lower pressures could be beneficial in preventing bleeding and swelling, and others prefer to keep levels higher. Our results have helped to give some guidance on this.”

Asked what he thought an optimum target would be, Dr. Anderson replied: “For now, I think a target of around 140 mm Hg systolic would be reasonable, and there is no evidence to move below that.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, a co-author of the ENCHANTED2/MT trial, also commented: “The real importance of these study results is that they show that lowering blood pressure too much is detrimental on outcome. My personal interpretation, looking at the results of this study but also on the previous studies, is that we should aim for a target of 140-150 mm Hg. This is true for patients with recanalization therapy. For patients without any therapy, I would even be more careful in lowering blood pressure and recommend just staying below 180 mm Hg.”

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

A large randomized trial that was investigating intensive lowering of blood pressure in acute ischemic stroke patients who had undergone mechanical thrombectomy has been stopped early because of safety concerns.

“Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischemic stroke due to intracranial large-vessel occlusion,” the investigators conclude.

Results from the ENCHANTED2/MT trial were presented by Craig Anderson, MD, professor of neurology and epidemiology, University of New South Wales, Sydney, during the 14th World Stroke Congress (WSC) in Singapore.

The study was simultaneously published online in The Lancet.

“What our results have pretty convincingly shown is that in acute stroke patients who have undergone mechanical thrombectomy, lowering blood pressure down to a systolic of 120 mm Hg for 3 days is too low for too long. We shouldn’t go that far down,” Dr. Anderson said in an interview.

Dr. Anderson said the trial has provided an important message for clinical practice.

“This result is not what we expected, but it is a definitive result and gives us a lower safety margin for blood pressure in acute ischemic stroke patients. This, in itself, is a big step forward.”

He noted that the optimum blood pressure for these patients is not known.

“We need to do further trials to determine optimum blood pressure in these acute patients, but perhaps we should be aiming more towards 140 mm Hg,” he suggested.

“But this trial shows us that in patients who have had successful clot retrieval with endovascular treatment for acute ischemic stroke, careful blood pressure management is important to avoid levels becoming too low. We have to make sure we don’t overshoot down to 120 mm Hg or below.”

The chair of the WSC session at which the trial was presented, Jeyaraj Pandian, MD, head of neurology at Christian Medical College, Ludhiana, India, who is the current vice-president of the World Stroke Organization, said: “This is a very important result. It has major practical implications.”

As background, Dr. Anderson explained that elevated blood pressure is very common in patients who have an acute ischemic stroke, and the higher the blood pressure, the higher the chances of having a worse outcome.

“Theoretically, if we can control the blood pressure, we may be able to improve outcomes,” he said.

In 2019, the first ENCHANTED trial reported that controlling blood pressure by a moderate amount – to around 140 mm Hg, which is lower than currently recommended in the guidelines – was linked to a reduction in bleeding complications of thrombolysis and appeared safe, but it did not improve recovery, Dr. Anderson noted.

“This trial was done before mechanical thrombectomy became routinely adopted, and this procedure has now become the standard of care for large-vessel occlusion strokes, but we don’t know what we should do about blood pressure in these patients,” he added.

A smaller French trial has suggested lowering blood pressure to 130 mm Hg, rather than a more liberal 130-180 mm Hg, was safe after successful mechanical thrombectomy, but there was no effect on functional outcome.

“In stroke patients with a large-vessel occlusion, blood pressure is often elevated to very high levels. There are wide ranges of opinions on what to do about this – whether it should be lowered, and by how much,” Dr. Anderson said. “We conducted the current ENCHANTED2/MT trial to look at this issue.”

The trial randomly assigned patients who had undergone successful mechanical clot retrieval and reperfusion but whose blood pressure was still elevated to two groups. In one group, blood pressure was aggressively lowered to less than 120 mm Hg within 1 hour of reperfusion, and blood pressure was kept at this level for 3 days. In the other group, a more liberal approach was used: Blood pressure was kept at 140-180 mm Hg.

The primary endpoint was disability, as measured by the Modified Rankin Scale (mRS) score at 90 days.

The study was started in China with the intention of expanding recruitment internationally. The planned enrollment was more than 2,000 patients.

However, in March of 2022, after 821 patients had been enrolled, the data safety monitoring board (DSMB) recommended that recruitment into the trial be suspended because of a safety signal. All of the patients who had been recruited were from China.

These patients were followed to obtain the 3-month outcome results, after which the DSMB recommended that the trial be stopped because safety was still a problem.

Mean systolic blood pressure was 125 mm Hg at 1 hour and 121 mm Hg at 24 hours in the more intensive-treatment group; it was 143 mm Hg at 1 hour and 139 mm Hg at 24 hours in the less intensive-treatment group, giving an adjusted mean difference over 24 hours of 18 mm Hg.
 

Worse disability scores

Results showed that the patients who underwent the more intensive blood pressure lowering had more disability at 3-month follow-up, with worse scores on a shift analysis of the mRS than those in the less intensive group (common odds ratio, 1.37; 95% confidence interval, 1.07-1.76).

The unfavorable shift in mRS scores in the more intensive group was consistent in adjusted sensitivity analysis, and there was no significant heterogeneity in the treatment effect on the primary outcome across all prespecified subgroups.

The incidence of death or neurologic deterioration at 7 days was higher in the more intensive-treatment group than the less intensive-treatment group (common OR, 1.53), and a between-group difference emerged at 24 hours.

The incidence of death or disability (mRS scores, 3-6) at 90 days was higher among patients in the more intensive-treatment group than the less intensive-treatment group (53% vs. 39%; OR, 1.85; P = .0001).

Among those who survived, more patients in the more intensive-treatment group had major disability (mRS scores, 3-5) at 90 days than did patients in the less intensive-treatment group (43% vs. 28%; OR, 2.07; P = .0001).
 

No difference in ICH or severe hypotension episodes

The incidence of symptomatic intracranial hemorrhage, mortality, and serious adverse events did not significantly differ between the two groups. There were no significant differences in recurrent ischemic stroke events at 90 days, and no episodes of severe hypotension were reported as a serious adverse event.

“Our results show that intensive lowering of blood pressure appears to be associated with worsening physical disability. While there was no difference in mortality rates between the two groups, the lower blood pressure appeared to compromise the ability to recover from the stroke,” Dr. Anderson said.

On the possible mechanism of harm, he suggested that the intensive blood pressure reduction might be interfering with blood flow through the injured part of the brain and impeding the ability to recover from the clot removal procedure.
 

What levels should be aimed for?

Dr. Anderson stressed that it was important to have conducted this trial.

“Current guidelines recommend very conservative level of blood pressure in acute ischemic stroke patients – to below 180 mm Hg. But no lower limit is recommended.

“Most clinicians aim for about the 140 mm Hg mark, but there is a large variation in opinion on what to do,” he said. “Some doctors treat aggressively, believing that lower pressures could be beneficial in preventing bleeding and swelling, and others prefer to keep levels higher. Our results have helped to give some guidance on this.”

Asked what he thought an optimum target would be, Dr. Anderson replied: “For now, I think a target of around 140 mm Hg systolic would be reasonable, and there is no evidence to move below that.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, a co-author of the ENCHANTED2/MT trial, also commented: “The real importance of these study results is that they show that lowering blood pressure too much is detrimental on outcome. My personal interpretation, looking at the results of this study but also on the previous studies, is that we should aim for a target of 140-150 mm Hg. This is true for patients with recanalization therapy. For patients without any therapy, I would even be more careful in lowering blood pressure and recommend just staying below 180 mm Hg.”

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

A large randomized trial that was investigating intensive lowering of blood pressure in acute ischemic stroke patients who had undergone mechanical thrombectomy has been stopped early because of safety concerns.

“Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischemic stroke due to intracranial large-vessel occlusion,” the investigators conclude.

Results from the ENCHANTED2/MT trial were presented by Craig Anderson, MD, professor of neurology and epidemiology, University of New South Wales, Sydney, during the 14th World Stroke Congress (WSC) in Singapore.

The study was simultaneously published online in The Lancet.

“What our results have pretty convincingly shown is that in acute stroke patients who have undergone mechanical thrombectomy, lowering blood pressure down to a systolic of 120 mm Hg for 3 days is too low for too long. We shouldn’t go that far down,” Dr. Anderson said in an interview.

Dr. Anderson said the trial has provided an important message for clinical practice.

“This result is not what we expected, but it is a definitive result and gives us a lower safety margin for blood pressure in acute ischemic stroke patients. This, in itself, is a big step forward.”

He noted that the optimum blood pressure for these patients is not known.

“We need to do further trials to determine optimum blood pressure in these acute patients, but perhaps we should be aiming more towards 140 mm Hg,” he suggested.

“But this trial shows us that in patients who have had successful clot retrieval with endovascular treatment for acute ischemic stroke, careful blood pressure management is important to avoid levels becoming too low. We have to make sure we don’t overshoot down to 120 mm Hg or below.”

The chair of the WSC session at which the trial was presented, Jeyaraj Pandian, MD, head of neurology at Christian Medical College, Ludhiana, India, who is the current vice-president of the World Stroke Organization, said: “This is a very important result. It has major practical implications.”

As background, Dr. Anderson explained that elevated blood pressure is very common in patients who have an acute ischemic stroke, and the higher the blood pressure, the higher the chances of having a worse outcome.

“Theoretically, if we can control the blood pressure, we may be able to improve outcomes,” he said.

In 2019, the first ENCHANTED trial reported that controlling blood pressure by a moderate amount – to around 140 mm Hg, which is lower than currently recommended in the guidelines – was linked to a reduction in bleeding complications of thrombolysis and appeared safe, but it did not improve recovery, Dr. Anderson noted.

“This trial was done before mechanical thrombectomy became routinely adopted, and this procedure has now become the standard of care for large-vessel occlusion strokes, but we don’t know what we should do about blood pressure in these patients,” he added.

A smaller French trial has suggested lowering blood pressure to 130 mm Hg, rather than a more liberal 130-180 mm Hg, was safe after successful mechanical thrombectomy, but there was no effect on functional outcome.

“In stroke patients with a large-vessel occlusion, blood pressure is often elevated to very high levels. There are wide ranges of opinions on what to do about this – whether it should be lowered, and by how much,” Dr. Anderson said. “We conducted the current ENCHANTED2/MT trial to look at this issue.”

The trial randomly assigned patients who had undergone successful mechanical clot retrieval and reperfusion but whose blood pressure was still elevated to two groups. In one group, blood pressure was aggressively lowered to less than 120 mm Hg within 1 hour of reperfusion, and blood pressure was kept at this level for 3 days. In the other group, a more liberal approach was used: Blood pressure was kept at 140-180 mm Hg.

The primary endpoint was disability, as measured by the Modified Rankin Scale (mRS) score at 90 days.

The study was started in China with the intention of expanding recruitment internationally. The planned enrollment was more than 2,000 patients.

However, in March of 2022, after 821 patients had been enrolled, the data safety monitoring board (DSMB) recommended that recruitment into the trial be suspended because of a safety signal. All of the patients who had been recruited were from China.

These patients were followed to obtain the 3-month outcome results, after which the DSMB recommended that the trial be stopped because safety was still a problem.

Mean systolic blood pressure was 125 mm Hg at 1 hour and 121 mm Hg at 24 hours in the more intensive-treatment group; it was 143 mm Hg at 1 hour and 139 mm Hg at 24 hours in the less intensive-treatment group, giving an adjusted mean difference over 24 hours of 18 mm Hg.
 

Worse disability scores

Results showed that the patients who underwent the more intensive blood pressure lowering had more disability at 3-month follow-up, with worse scores on a shift analysis of the mRS than those in the less intensive group (common odds ratio, 1.37; 95% confidence interval, 1.07-1.76).

The unfavorable shift in mRS scores in the more intensive group was consistent in adjusted sensitivity analysis, and there was no significant heterogeneity in the treatment effect on the primary outcome across all prespecified subgroups.

The incidence of death or neurologic deterioration at 7 days was higher in the more intensive-treatment group than the less intensive-treatment group (common OR, 1.53), and a between-group difference emerged at 24 hours.

The incidence of death or disability (mRS scores, 3-6) at 90 days was higher among patients in the more intensive-treatment group than the less intensive-treatment group (53% vs. 39%; OR, 1.85; P = .0001).

Among those who survived, more patients in the more intensive-treatment group had major disability (mRS scores, 3-5) at 90 days than did patients in the less intensive-treatment group (43% vs. 28%; OR, 2.07; P = .0001).
 

No difference in ICH or severe hypotension episodes

The incidence of symptomatic intracranial hemorrhage, mortality, and serious adverse events did not significantly differ between the two groups. There were no significant differences in recurrent ischemic stroke events at 90 days, and no episodes of severe hypotension were reported as a serious adverse event.

“Our results show that intensive lowering of blood pressure appears to be associated with worsening physical disability. While there was no difference in mortality rates between the two groups, the lower blood pressure appeared to compromise the ability to recover from the stroke,” Dr. Anderson said.

On the possible mechanism of harm, he suggested that the intensive blood pressure reduction might be interfering with blood flow through the injured part of the brain and impeding the ability to recover from the clot removal procedure.
 

What levels should be aimed for?

Dr. Anderson stressed that it was important to have conducted this trial.

“Current guidelines recommend very conservative level of blood pressure in acute ischemic stroke patients – to below 180 mm Hg. But no lower limit is recommended.

“Most clinicians aim for about the 140 mm Hg mark, but there is a large variation in opinion on what to do,” he said. “Some doctors treat aggressively, believing that lower pressures could be beneficial in preventing bleeding and swelling, and others prefer to keep levels higher. Our results have helped to give some guidance on this.”

Asked what he thought an optimum target would be, Dr. Anderson replied: “For now, I think a target of around 140 mm Hg systolic would be reasonable, and there is no evidence to move below that.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, a co-author of the ENCHANTED2/MT trial, also commented: “The real importance of these study results is that they show that lowering blood pressure too much is detrimental on outcome. My personal interpretation, looking at the results of this study but also on the previous studies, is that we should aim for a target of 140-150 mm Hg. This is true for patients with recanalization therapy. For patients without any therapy, I would even be more careful in lowering blood pressure and recommend just staying below 180 mm Hg.”

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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