Lipid Disorders

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

PHILADELPHIA – Treating patients to a lower LDL target after an ischemic stroke of atherosclerotic origin resulted in fewer recurrent strokes or major cardiovascular events, compared with a higher LDL goal, even though the international trial was stopped early because of lack of funding.

“In the Treat Stroke to Target [TST] trial we showed that the group of patients with an atherosclerotic stroke achieving an LDL cholesterol of less than 70 mg/dL had 22% less recurrent ischemic stroke or other major vascular events than the group achieving a LDL cholesterol between 90 and 110 mg/dL,” lead author Pierre Amarenco, MD, chairman of the department of neurology and the stroke center at Bichat Hospital in Paris, said in an interview.

“We avoided more than one in recurrence in five,” he added.

The findings of the investigator-initiated trial were reported during a late-breaking research session at the American Heart Association scientific sessions and simultaneously published online Nov. 18 in the New England Journal of Medicine (doi: 10.1056/NEJMoa1910355).

Discussant Mitchell S.V. Elkind, MD, president-elect of the American Heart Association, called the TST findings “practice confirming” of a strategy many cardiologists already follow for stroke patients.

“The TST study is only the second trial that was done in neurology for stroke prevention using statins and lipid-lowering therapy, and that’s what makes it a hopeful and real advance,” he said in an interview.

To achieve the LDL-lowering goal, two-thirds of patients received a high-dose statin therapy while the remainder received both high-dose statin and ezetimibe (Zetia, Merck). There were no significant increases in intracranial hemorrhage observed between lower- and higher-target groups.

“Now guidelines should move to recommending a target LDL cholesterol of less than 70 mg/dL in all patients with a proven ischemic stroke of atherosclerotic origin,” said Dr. Amarenco, who is also a professor of neurology at Denis Diderot Paris University.

Rare lipid study following stroke

American Heart Association/American Stroke Association guidelines recommend intense statin therapy after an atherothrombotic stroke “but no target level is given to the practitioners,” Dr. Amarenco said. “In reality, most patients receive a reduced dose of statin.”

For example, despite 70% of patients receiving a statin, the average LDL cholesterol level was 92 mg/dL in a real-world registry.

The TST trial is the first major study to evaluate treating to target LDL levels in the ischemic stroke population since the SPARCL trial in 2006. SPARCL was the first randomized, controlled clinical trial to evaluate whether daily statin therapy could reduce the risk of stroke in patients who had suffered a stroke or transient ischemic attack (TIA).

SPARCL demonstrated a 16% risk reduction with atorvastatin 80 mg daily versus placebo, and further risk reduction of 33% among those with carotid stenosis, over 5 years. There was some concern about safety for a time; post-hoc analysis showed what appeared to be an increased risk for intracranial hemorrhage with statin treatment. Subsequent analyses seemed to suggest the finding may have been a chance one, however.

For the TST study, Dr. Amarenco and colleagues enrolled participants between March 2010 and December 2018 at one of 61 centers in France. In 2015, the study expanded to include 16 sites in South Korea.

Investigators evaluated participants after an ischemic stroke or a TIA with evidence of atherosclerosis. Blood pressure, smoking cessation, and diabetes were well controlled, he said.

Dr. Amarenco and colleagues randomly assigned 1,430 participants to the low–LDL cholesterol target group, less than 70 mg/dL, and another 1,430 to a high-LDL group with a target of 100 mg/dL.

Assessments were every 6 months and up to 1 year after the last patient joined the study.

Treatment with any available statin on the market was allowed. Ezetimibe could be added on top of statin therapy as necessary. A total of 55% were statin naive at study entry.

Study stopped early

The trial was stopped in May 2019 after allocated funds ran out. At this point, researchers had 277 events to analyze, although their initial goal was to reach 385.

The primary endpoint of this event-driven trial was a composite of nonfatal stroke, nonfatal MI, and unstable angina followed by urgent coronary revascularization; TIA followed by urgent carotid revascularization; or cardiovascular death, including sudden deaths.

The endpoint was experienced by 8.5% of participants in the lower-target group versus 10.9% of those in the higher-target group. This translated to a 22% relative risk reduction (adjusted hazard ratio, 0.78; 95% confidence interval, 0.68-0.98; P =.04).

A total of 86% of participants had an ischemic stroke confirmed by brain MRI or CT scan. In this group, the relative risk reduction was 33% – “meaning that we could avoid one-third of recurrent major vascular events,” Dr. Amarenco said.

Furthermore, targeting the lower LDL levels was associated with a relative risk reduction of 40% among those with diabetes.

Secondary outcomes not significant

The investigators used hierarchical testing to compare two outcomes at a time in a prespecified order. They planned to continue this strategy until a comparison emerged as nonsignificant.

This occurred right away when their first composite secondary endpoint comparison between nonfatal MI and urgent revascularization was found to be not significantly different between groups (P = .12).

The early ending “weakened the results of the trial, and the results should be taken with caution because of that,” Dr. Amarenco said.

In addition, the number of hemorrhagic strokes did not differ significantly between groups. There were 18 of these events in the lower-target group and 13 in the higher-target cohort.

That numerical increase in intracranial hemorrhage was “driven by the Korean patients. … and that is something we will report soon,” Dr. Amarenco said.

Interestingly, the researchers also evaluated how much time participants spent within the target LDL cholesterol range, averaged by study site. They found that 53% of the lower–LDL target group, for example, was in the therapeutic range on average during the study.

When Dr. Amarenco and colleagues looked at participants who managed to spend 50%-100% in the target range, the relative risk reduction was 36%.

“So we can hypothesize that, if we had used a more potent drug like PCSK9 inhibitors to be closer to 100% in the therapeutic range, we may have had a greater effect size,” Dr. Amarenco said.

“Our results suggest that LDL cholesterol is causally related to atherosclerosis and confirm that the lower the LDL cholesterol the better,” Dr. Amarenco said.

“Future trials should explore the efficacy and safety of lowering LDL cholesterol to very low levels such as less than 55 mg/dL or even 30 mg/dL (as obtained in the FOURIER trial) by using PCSK9 inhibitors or equivalent in patients with an ischemic stroke due to atherosclerotic disease,” Dr. Amarenco said.

‘Practice-confirming’ findings

The findings are also in line with secondary analyses of the WASID (Neurology. 1995 Aug;45[8]:1488-93) and SAMMPRIS trials, which should dispel some concerns that persist about taking LDL to such low levels that it increases risk of intracerebral hemorrhage, Dr. Amarenco noted.

However, TST, he said, didn’t provide clear answers on what specific subgroups of patients with a stroke history would benefit from aggressive lipid lowering.

“What is stroke without atherosclerotic disease?” he said. “Some people say small-vessel disease is also a form of atherosclerosis, and most patients with atrial fibrillation, which is increasingly recognized as a cause of stroke, are also going to have atherosclerosis of the heart as well as the brain and blood vessels.

“Many, many stroke patients will fall into this category,” Dr. Elkind said, “and the question is, should they be treated more aggressively with lipid lowering?”

“The results of this study fit pretty nicely into the rubric of the AHA cholesterol guidelines,” said Donald M. Lloyd-Jones, MD, chairman, department of preventive medicine at Northwestern University Feinberg School of Medicine, Chicago, and chair of the AHA’s 2019 Council on Scientific Sessions Programming. Dr. Lloyd-Jones was also a member of the guideline committee.

Stroke patients are not “garden variety coronary patients,” he said. “The concern about intracerebral hemorrhage continues to be something that we wonder about: Should we be driving our stroke patients as low as our coronary patients? I think these data will certainly help us.”

Consideration for future guidelines

The study would have been more helpful if it provided more detail about the treatment regimens used, Jennifer Robinson, MD, director of the prevention intervention center, department of epidemiology, University of Iowa, said in an interview.

“What was the dose intensity of statins the patients were on?” Dr. Robinson said. “Part of our struggle has been to convince people to use high-intensity statins – get the maximum from statins that are generic now and cost saving in even very low-risk primary prevention patients.”

She said that a third of patients in TST also took ezetimibe with the statin “makes sense” because of its generic status.

Nonetheless, Dr. Robinson said, TST adds to the evidence that LDL of 100 mg/dL is not good enough, that high-intensity statin therapy is superior to a moderate regimen and that adding a nonstatin – ezetimibe in TST – can derive added benefit.

The TST findings may give guideline writers direction going forward, she said. “We really need to start thinking about the potential for net benefit from added therapy, whether it’s from intensifying LDL lowering, adding icosapent ethyl (Vascepa, Amarin), which seems to have remarkable benefits, or SGLT2 inhibitor,” she said.

“There are a lot of options,” Dr. Robinson said. “We need to have an outlook beyond just treating to target with what really is the best maximized accepted therapy.”

TST was funded primarily by French Government, but also with grants from Pfizer, Astra Zeneca and Merck. Dr. Amarenco disclosed that he is a consultant or advisor to Modest, Sanofi, Bristol-Myers Squibb, and Amgen; receives honoraria from Modest, Amgen, Kowa, Shing Poon, Kowa, Bayer, GSK, Fibrogen, and AstraZeneca. He also receives research grants from Pfizer, Astra Zeneca, Sanofi, BMS, Merck, Boston Scientific, and the French Government.

This article also appears on Medscape.com.

SOURCE: Amarenco P. ACC 2019, Late Breaking Science 6 session.

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.

Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.

The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.

Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.

[email protected]

PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.

Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.

The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.

Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.

[email protected]

PHILADELPHIA – A novel treatment strategy tackling hypertriglyceridemia via long-acting agents targeting two specific culprit genes caused a stir based on the highly encouraging early results of two small proof-of-concept studies presented at the American Heart Association scientific sessions.

Bruce Jancin/MDedge News

ARO-APOC3 is a small interfering ribonucleic acid molecule (siRNA) targeting the apolipoprotein C-III gene (APOC3) specifically within hepatocytes, while ARO-ANG3 is an siRNA targeting hepatic angiotensinlike protein 3 (ANG3). ARO-APOC3 is being developed as a potential treatment for familial chylomicronemia syndrome, a rare disorder associated with triglyceride levels in excess of 800 mg/dL, as well as for patients with severe hypertriglyceridemia and associated pancreatitis – a far more common condition – and ultimately, perhaps, for patients with hypertriglyceridemia and heart disease. ARO-ANG3, which lowers very-low-density lipoprotein (VLDL) as well as LDL cholesterol while increasing HDL cholesterol levels, is under development as a treatment for high triglycerides, homozygous familial hypercholesterolemia, nonalcoholic fatty liver disease, and metabolic diseases.

Christie M. Ballantyne, MD, presented the results of the phase 1/2a study of ARO-APOC3, which included 40 healthy subjects who received a single subcutaneous injection of the RNA inhibitor at 10, 25, 50, or 100 mg and were followed for 16 weeks. At the highest dose, it reduced serum APOC3 levels by 94%, triglyceride levels by 64%, LDL cholesterol levels by up to 25%, and VLDL by a maximum of 68%, while boosting HDL cholesterol levels by up to 69%. These substantial changes in lipids remained stable through week 16.

The observed prolonged duration of effect provides a potential opportunity for dosing quarterly or perhaps even twice a year. This would be ideal for patients who have problems with adherence to daily therapy with statins and other oral agents, observed Dr. Ballantyne, professor of medicine and professor of molecular and human genetics at Baylor College of Medicine, Houston.

Bruce Jancin/MDedge News

Bruce Jancin/MDedge News

Dr. Rader commented that plenty of questions remain to be answered about siRNA therapy for hyperlipidemia. These include which target – APOC3 or ANG3 – is the more effective for treating severe hypertriglyceridemia and/or for preventing major cardiovascular events, how frequently these agents will need to be dosed, whether there’s a clinical downside to the substantial HDL cholesterol lowering seen with silencing of ANG3, and whether the APOC3 that’s produced in the intestine – and which isn’t touched by hepatocentric ARO-APOC3 – will cause problems.

Dr. Ballantyne reported serving as a consultant to Arrowhead Pharmaceutics, which is developing the RNA inhibitors for hypertriglyceridemia, as well as numerous other pharmaceutical companies. Dr. Watts has received research grants from Amgen and Sanofi-Regeneron.

[email protected]

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

Icosapent ethyl, a highly purified form of the ethyl ester of eicosapentaenoic acid, received unanimous backing from a Food and Drug Administration advisory panel for a new indication for reducing cardiovascular event risk.

Icosapent ethyl (Vascepa) received initial agency approval in 2012 for the indication of cutting triglyceride levels once they reached at least 500 mg/dL.

The target patient population for this new, cardiovascular-event protection role will reflect some or all of the types of patients enrolled in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial), which tested icosapent ethyl in 8,179 patients with either established cardiovascular disease or diabetes and at least one additional cardiovascular disease risk factor. This study provided the bulk of the data considered by the FDA panel.

REDUCE-IT showed that, during a median of 4.9 years, patients who received icosapent ethyl had a statistically significant 25% relative risk reduction in the trial’s primary, composite endpoint (New Engl J Med. 2019 Jan 3;380[1]:11-22).

Icosapent ethyl “appeared effective and safe,” and would be a “useful, new, added agent for treating patients” like those enrolled in the trial, said Kenneth D. Burman, MD, professor and chief of endocrinology at Medstar Washington (D.C.) Hospital Center and chair of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

The advisory panel members appeared uniformly comfortable with recommending that the FDA add a cardiovascular disease indication based on the REDUCE-IT findings.

But while they agreed that icosapent ethyl should receive some type of indication for cardiovascular event reduction, the committee split over which patients the indication should include. Specifically, they diverged on the issue of primary prevention.

Some said that the patient enrollment that produced a positive result in REDUCE-IT should not be retrospectively subdivided, while others said that combining secondary- and primary-prevention patients in a single large trial inappropriately lumped together patients who would be better considered separately.

Committee members also expressed uncertainty over the appropriate triglyceride level to warrant treatment. The REDUCE-IT trial was designed to enroll patients with triglycerides of 135 mg/dL or greater, but several panel members suggested that, for labeling, the threshold should be at least 150 mg/dL, or even 200 mg/dL.

Safety was another aspect that generated a lot of panel discussion throughout their day-long discussion, with particular focus on a signal of a small but concerning increased rate of incident atrial fibrillation among patients who received icosapent ethyl, as well as a small but nearly significant increase in the rate of serious bleeds.

Further analyses presented during the meeting showed that an increased bleeding rate linked with icosapent ethyl was focused in patients who concurrently received one or more antiplatelet drugs or an anticoagulant.

However, panel members rejected the notion that these safety concerns warranted a boxed warning, agreeing that it could be managed with appropriate labeling information.

Clinician reaction

Clinicians who manage these types of patients viewed the prospect of an expanded indication for icosapent ethyl as an important advance.

The REDUCE-IT results by themselves “were convincing” for patients with established cardiovascular disease without need for a confirmatory trial, Robert H. Eckel, MD, an endocrinologist and professor of medicine at the University of Colorado at Denver, Aurora, said in an interview. But he remained unconvinced about efficacy for primary-prevention patients, or even for secondary-prevention patients with a triglyceride level below 150 mg/dL.

“Icosapent ethyl will clearly be a mainstay for managing high-risk patients. It gives us another treatment option,” Yehuda Handelsman, MD, an endocrinologist and medical director and principal investigator of the Metabolic Institute of America in Tarzana, Calif., said in an interview. “I do not see the atrial fibrillation or bleeding effects as reasons not to approve this drug. It should be a precaution. Overall, icosapent ethyl is one of the easier drugs for patients to take.”

Dr. Handelsman said it would be unethical to run a confirmatory trial and randomize patients to placebo. “Another trial makes no sense,” he said.

But the data from REDUCE-IT were “not as convincing” for primary-prevention patients, suggesting a need for caution about using icosapent ethyl for patients without established cardiovascular disease, Paul S. Jellinger, MD, an endocrinologist in Fort Lauderdale, Fla., said in an interview.

Cost-effectiveness

An analysis of the cost-effectiveness of icosapent ethyl as used in REDUCE-IT showed that the drug fell into the rare category of being a “dominant” treatment, meaning that it both improved patient outcomes and reduced medical costs. William S. Weintraub, MD, will report findings from this analysis on Nov. 16, 2019, at the annual scientific sessions of the American Heart Association.

The analysis used a wholesale acquisition cost for a 1-day dosage of icosapent ethyl of $4.16, derived from a commercial source for prescription-drug pricing and actual hospitalization costs for the patients in the trial.

Based on the REDUCE-IT outcomes, treatment with icosapent ethyl was linked with a boost in quality-adjusted life-years that extrapolated to an average 0.26 increase during the full lifetime of REDUCE-IT participants, at a cost that averaged $1,284 less per treated patient over their lifetime, according to Dr. Weintraub, director of Outcomes Research at Medstar Washington Hospital Center, Washington.

Although the 0.26 lifetime increase in quality-adjusted life-years may sound modest, “in the cost-effectiveness world, 0.26 is actually significant,” Dr. Weintraub said. He also highlighted how unusual it is to find a patented drug that improves quality of life and longevity while also saving money.

“I know of no other on-patent, branded pharmaceutical that is dominant,” he said.

Off-patent pharmaceuticals, like statins, can be quite inexpensive and may also be dominant, he noted. Being dominant for cost-effectiveness means that icosapent ethyl “provides good value and is worth what we pay for it, well within social thresholds of willingness to pay,” Dr. Weintraub said.

REDUCE-IT was sponsored by Amarin, the company that markets icosapent ethyl (Vascepa). Dr. Burman has received research funding from AstraZeneca, Eisai, and IBSA. Dr. Eckel has received personal fees from Kowa Pharmaceuticals, Merck, Novartis, and Sanofi/Regeneron, as well as research funding from Endece, Ionis Pharmaceuticals, and UniQure. Dr. Handelsman has been a consultant to and received research funding from Amarin and several other companies. Dr. Jellinger has been a speaker on behalf of Amarin, Amgen, and Regeneron. Dr. Weintraub has received honoraria and research support from Amarin, and honoraria from AstraZeneca.

[email protected]

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

[email protected]

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

[email protected]

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

When added to maximally tolerated statin therapy, bempedoic acid reduced LDL cholesterol by more than 15%, compared with placebo, Anne C. Goldberg, MD, and colleagues reported in JAMA.

The prodrug also improved non-HDL cholesterol, total cholesterol, apolipoprotein B, and C-reactive protein in a group of patients who remained at high risk of cardiovascular events despite maximally tolerated statin treatment, said Dr. Goldberg of Washington University, St. Louis, and coauthors in reporting the results of CLEAR Wisdom (Evaluation of Long-Term Efficacy of Bempedoic Acid [ETC-1002] in Patients With Hyperlipidemia at High Cardiovascular Risk).

The prodrug bempedoic acid works differently than most statins. In the liver, the drug activates into bempedoyl-CoA. It interrupts ATP-citrate lyase, an enzyme critical to the main statin target, 3-hydroxy-3-methylglutaryl-CoA reductase. Although it reduces cholesterol synthesis in the liver, bempedoic acid isn’t active in skeletal muscle, unlike statins.

The 52-week placebo-controlled trial included 2,300 patients enrolled at 91 international sites. All of them had atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. They were randomized 2:1 to bempedoic acid 180 mg daily or placebo. Patients were a mean of 64 years old, with a mean LDL cholesterol level of 120.4 mg/dL. Most (89.6%) were receiving statin therapy, with 53% receiving high-intensity treatment.

The primary endpoint was change in LDL cholesterol. Secondary measures included overall lipid changes and changes in lipoprotein and biomarkers of cardiovascular disease.

After 12 weeks, patients taking bempedoic acid experienced significantly lowered LDL cholesterol, compared with those taking placebo (–15% vs. 2.4%; between-group difference, 17.4%). The key secondary endpoints were also positive, including non–LDL cholesterol (–10.8% vs. 2.3%), total cholesterol (–9.9% vs. 1.3%), apolipoprotein B (–9.3% vs 3.7%), and high-sensitivity C-reactive protein (median, –18.7% vs –9.4%)

Most patients in both groups (about 70%) experienced at least one adverse event. However, the majority of those (77.6%) were not related to the study drug. Most were mild to moderate and included myalgia (1% vs. 0.8%), increased aspartate aminotransferase level (0.6% vs. 0%), and arthralgia (0.6% vs. 0%).

Serious adverse events occurred in 19.8% of patients, with three possibly related to bempedoic acid. These were ulcerative colitis and ischemic stroke in the bempedoic acid group and upper abdominal pain in the placebo group.

Eight fatalities occurred during the CLEAR Wisdom. There were single cases of cardiac arrest, coronary artery arteriosclerosis, acute poisoning with carbon dioxide, myocardial infarction, and septic shock related to a prescheduled abdominal surgical procedure. One patient in the active group died from an unknown cause.

Four events in the bempedoic acid group and two events in the placebo group were cardiovascular deaths.

New or worsening diabetes developed in approximately 7% of each group, and less than 3% of those taking bempedoic acid developed gout or increased blood uric acid, as was the case for less than 1% of patients taking placebo.

In May, the Food and Drug Administration accepted a New Drug Application from Esperion for bempedoic acid. A response is expected in February 2020.

Dr. Goldberg reporter receiving research grants/support from Amgen, Amarin, Pfizer, Regeneron, Sanofi, IONIS, Novartis, and Merck and serving as a consultant for Esperion, Novartis, Akcea, OptumRX, 23andMe, Sanofi/Regeneron, and Merck.

[email protected]

SOURCE: Goldberg AC et al. JAMA. 2019 Nov 12;322:1780-8.

Statins started in childhood for patients with familial hypercholesterolemia reduced progression of carotid thickening and cut the risk of cardiovascular disease 20 years later, according to authors of a long-term follow-up study.

There were no deaths and one cardiovascular event by the age of 39 years for patients in the observational study who had, as children, participated in a placebo-controlled, 2-year safety and efficacy study of pravastatin.

These positive effects on disease and a disease marker (carotid intima-media thickness) were observed even though only 20% of patients met LDL cholesterol goals, according to study senior authors John J.P. Kastelein, MD, PhD, and Barbara A. Hutten, PhD, of Amsterdam University Medical Centers in the Netherlands, and their colleagues.

“If corroborated, such findings would underscore the current pediatric guidelines, which recommend starting treatment from the age of 8 years or 10 years, with less-stringent targets than those for adults,” the investigators wrote in the report, which was published in the New England Journal of Medicine.

The study was based in part on follow-up visits with 184 of the original cohort of 214 patients with familial hypercholesterolemia in the 2-year pravastatin study, along with 77 of 95 unaffected siblings who had served as a control group in that study.

At the time of the 20-year follow-up, 79% of the familial hypercholesterolemia patients said they were using lipid-lowering medication, the investigators wrote.

The mean LDL cholesterol level at follow-up was 160.7 mg/dL for those with familial hypercholesterolemia, a drop of 32% when compared with the mean LDL cholesterol level at baseline in the original study, according to the investigators. By contrast, LDL cholesterol in the unaffected siblings was 121.9 mg/dL, up 24% from baseline.

Just 37 patients with familial hypercholesterolemia, or about 20%, reached the LDL cholesterol treatment target of less than 100 mg/dL, the investigators wrote.

At the start of the original trial, carotid intima-media thickness was greater in patients with familial hypercholesterolemia, compared with their unaffected siblings, with a mean difference of 0.012 mm (95% confidence interval, 0.002-0.021) after adjustment for age and sex.

Some 20 years later, the mean difference in thickness for patients with familial hypercholesterolemia and unaffected siblings, was 0.555 mm and 0.551 mm, respectively, for a mean difference of just 0.008 mm (95% CI, –0.009 to 0.026) after adjustments.

Data on cardiovascular events and deaths for affected parents was collected, as each child in the study had a parent with confirmed familial hypercholesterolemia, the investigators wrote.

A total of 7% of affected parents had died of MI before the age of 40 years, whereas there were no deaths from cardiovascular causes in all 214 patients with familial hypercholesterolemia from the original study.

Similarly, about a quarter of affected parents had a cardiovascular event before age 40, whereas there was only one event recorded in the patients in the study. That event, angina pectoris resulting in percutaneous coronary intervention, occurred in a patient who stopped taking the drug at the end of the trial, the investigators wrote.

The study was supported by a grant from the AMC Foundation. The study authors reported disclosures related to numerous pharmaceutical companies and government, nonprofit, or academic entities.

SOURCE: Kastelein JJP et al. N Engl J Med. 2019;381:1547-56.

Statins started in childhood for patients with familial hypercholesterolemia reduced progression of carotid thickening and cut the risk of cardiovascular disease 20 years later, according to authors of a long-term follow-up study.

There were no deaths and one cardiovascular event by the age of 39 years for patients in the observational study who had, as children, participated in a placebo-controlled, 2-year safety and efficacy study of pravastatin.

These positive effects on disease and a disease marker (carotid intima-media thickness) were observed even though only 20% of patients met LDL cholesterol goals, according to study senior authors John J.P. Kastelein, MD, PhD, and Barbara A. Hutten, PhD, of Amsterdam University Medical Centers in the Netherlands, and their colleagues.

“If corroborated, such findings would underscore the current pediatric guidelines, which recommend starting treatment from the age of 8 years or 10 years, with less-stringent targets than those for adults,” the investigators wrote in the report, which was published in the New England Journal of Medicine.

The study was based in part on follow-up visits with 184 of the original cohort of 214 patients with familial hypercholesterolemia in the 2-year pravastatin study, along with 77 of 95 unaffected siblings who had served as a control group in that study.

At the time of the 20-year follow-up, 79% of the familial hypercholesterolemia patients said they were using lipid-lowering medication, the investigators wrote.

The mean LDL cholesterol level at follow-up was 160.7 mg/dL for those with familial hypercholesterolemia, a drop of 32% when compared with the mean LDL cholesterol level at baseline in the original study, according to the investigators. By contrast, LDL cholesterol in the unaffected siblings was 121.9 mg/dL, up 24% from baseline.

Just 37 patients with familial hypercholesterolemia, or about 20%, reached the LDL cholesterol treatment target of less than 100 mg/dL, the investigators wrote.

At the start of the original trial, carotid intima-media thickness was greater in patients with familial hypercholesterolemia, compared with their unaffected siblings, with a mean difference of 0.012 mm (95% confidence interval, 0.002-0.021) after adjustment for age and sex.

Some 20 years later, the mean difference in thickness for patients with familial hypercholesterolemia and unaffected siblings, was 0.555 mm and 0.551 mm, respectively, for a mean difference of just 0.008 mm (95% CI, –0.009 to 0.026) after adjustments.

Data on cardiovascular events and deaths for affected parents was collected, as each child in the study had a parent with confirmed familial hypercholesterolemia, the investigators wrote.

A total of 7% of affected parents had died of MI before the age of 40 years, whereas there were no deaths from cardiovascular causes in all 214 patients with familial hypercholesterolemia from the original study.

Similarly, about a quarter of affected parents had a cardiovascular event before age 40, whereas there was only one event recorded in the patients in the study. That event, angina pectoris resulting in percutaneous coronary intervention, occurred in a patient who stopped taking the drug at the end of the trial, the investigators wrote.

The study was supported by a grant from the AMC Foundation. The study authors reported disclosures related to numerous pharmaceutical companies and government, nonprofit, or academic entities.

SOURCE: Kastelein JJP et al. N Engl J Med. 2019;381:1547-56.

Statins started in childhood for patients with familial hypercholesterolemia reduced progression of carotid thickening and cut the risk of cardiovascular disease 20 years later, according to authors of a long-term follow-up study.

There were no deaths and one cardiovascular event by the age of 39 years for patients in the observational study who had, as children, participated in a placebo-controlled, 2-year safety and efficacy study of pravastatin.

These positive effects on disease and a disease marker (carotid intima-media thickness) were observed even though only 20% of patients met LDL cholesterol goals, according to study senior authors John J.P. Kastelein, MD, PhD, and Barbara A. Hutten, PhD, of Amsterdam University Medical Centers in the Netherlands, and their colleagues.

“If corroborated, such findings would underscore the current pediatric guidelines, which recommend starting treatment from the age of 8 years or 10 years, with less-stringent targets than those for adults,” the investigators wrote in the report, which was published in the New England Journal of Medicine.

The study was based in part on follow-up visits with 184 of the original cohort of 214 patients with familial hypercholesterolemia in the 2-year pravastatin study, along with 77 of 95 unaffected siblings who had served as a control group in that study.

At the time of the 20-year follow-up, 79% of the familial hypercholesterolemia patients said they were using lipid-lowering medication, the investigators wrote.

The mean LDL cholesterol level at follow-up was 160.7 mg/dL for those with familial hypercholesterolemia, a drop of 32% when compared with the mean LDL cholesterol level at baseline in the original study, according to the investigators. By contrast, LDL cholesterol in the unaffected siblings was 121.9 mg/dL, up 24% from baseline.

Just 37 patients with familial hypercholesterolemia, or about 20%, reached the LDL cholesterol treatment target of less than 100 mg/dL, the investigators wrote.

At the start of the original trial, carotid intima-media thickness was greater in patients with familial hypercholesterolemia, compared with their unaffected siblings, with a mean difference of 0.012 mm (95% confidence interval, 0.002-0.021) after adjustment for age and sex.

Some 20 years later, the mean difference in thickness for patients with familial hypercholesterolemia and unaffected siblings, was 0.555 mm and 0.551 mm, respectively, for a mean difference of just 0.008 mm (95% CI, –0.009 to 0.026) after adjustments.

Data on cardiovascular events and deaths for affected parents was collected, as each child in the study had a parent with confirmed familial hypercholesterolemia, the investigators wrote.

A total of 7% of affected parents had died of MI before the age of 40 years, whereas there were no deaths from cardiovascular causes in all 214 patients with familial hypercholesterolemia from the original study.

Similarly, about a quarter of affected parents had a cardiovascular event before age 40, whereas there was only one event recorded in the patients in the study. That event, angina pectoris resulting in percutaneous coronary intervention, occurred in a patient who stopped taking the drug at the end of the trial, the investigators wrote.

The study was supported by a grant from the AMC Foundation. The study authors reported disclosures related to numerous pharmaceutical companies and government, nonprofit, or academic entities.

SOURCE: Kastelein JJP et al. N Engl J Med. 2019;381:1547-56.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

[email protected]

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

[email protected]

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Over the course of years and decades, lower LDL cholesterol levels and lower systolic blood pressure can reduce the lifetime risk of cardiovascular disease by up to 80%, according to a new study.

SilverV/thinkstockphotos

“What we found is that lifetime exposure to the combination of lower LDL and lower systolic blood pressure is associated with independent, additive, and dose-dependent effects on the lifetime risk of cardiovascular disease,” said the study’s senior author, Brian Ference, MD, speaking at the annual congress of the European Society of Cardiology. “The data seem to confirm that most cardiovascular events are preventable, and suggest that most cardiovascular events can be prevented, with prolonged exposure to modestly lower LDL cholesterol and systolic blood pressure.”

Any reduction of LDL-C and systolic blood pressure (SBP), in any combination, was associated with a lower lifetime risk of cardiovascular disease (CVD) in the study, which took advantage of the United Kingdom’s large Biobank to identify individuals with genetically lower LDL-C and blood pressure levels. The relationship was dose-dependent and showed a log-linear relationship to the combined absolute LDL-C and SBP differences, said Dr. Ference, professor and executive director of the Centre for Naturally Randomised Trials at the University of Cambridge, England.

The results validate current guidelines that focus on a lifetime approach to cardiovascular risk reduction and support a focus on therapeutic lifestyle interventions for individuals at all levels of risk for cardiovascular events, said Dr. Ference. He foresees the results shaping new risk-estimating algorithms and informing the next round of prevention guidelines.

Previous studies had suggested that long-term exposure to lower levels of LDL-C and lower systolic blood pressure reduced cardiovascular risk, but the association hadn’t been fully quantified. Ideally, said Dr. Ference, the question would be answered by a long-term randomized controlled trial, but it would be decades before meaningful data would accrue, and such a trial is unlikely to be conducted.

Using data from 438,952 Biobank participants, Dr. Ference and coinvestigators sought to quantify the association between LDL-C, systolic blood pressure, and atherosclerotic CVD. Taking advantage of genetic variants known to be associated with both lower LDL-C and lower systolic blood pressure, the researchers constructed a “natural randomization” trial. This trial design is also known as Mendelian randomization.

First, the entire study population was randomized into those with exome variants associated with higher or lower LDL-C, which resulted in a mean 15-mg/dL difference between the arms. Then, each LDL-C arm was randomized into groups with exome variants associated with higher or lower SBP, resulting in a difference of 2.9-3 mm Hg between the blood pressure arms within each LDL arm. This randomization yielded a reference group, a group with lower LDL-C, a group with lower SBP, and a group with lower LDL-C and SBP.

For the total population, the mean LDL-C was 138 mg/dL, and the mean SBP was 137.8 mm Hg.

A total of 24,980 participants had coronary revascularization, a nonfatal myocardial infarction (MI), or coronary death – the composite primary outcome measure of major coronary events.

“What we found is that long-term exposure to the combination of 1 mmol/L [about 39 mg/dL] lower LDL and 10 mm/Hg lower blood pressure is associated with an 80% lifetime reduction in risk of cardiovascular events, a 75% reduction in the risk of MI, and 68% reduction in the long-term risk of cardiovascular death,” said Dr. Ference.

By breaking participants out into separate quartiles of LDL-C and SBP levels, and examining outcomes for each quartile independently, Dr. Ference and collaborators were able to ascertain that the salutary effects of lower LDL-C and SBP were independent of each other.

Looking at individual cardiovascular outcomes, “The effect of combined exposure to both lower LDL and lower systolic blood pressure appear to be quite similar across multiple composite cardiovascular outcomes,” said Dr. Ference; benefit was seen in risk of MI, stroke, and other vascular events.

Plotting out the amount of risk reduction against the genetic scores for LDL-C and SBP reduction showed a proportional relationship that was logarithmically linear. “These large proportional reductions in risk really suggest that, for LDL, systolic blood pressure, and their combination, the benefit really depends both on the magnitude and the duration of the exposure,” said Dr. Ference. The effect was seen regardless of age, gender, body mass index, and diabetes status; being a smoker slightly attenuated the effects of LDL-C and SBP.

The mean participant age was 65 years, and women made up 54% of the study population. Aside from lipid values and systolic blood pressure, there were no significant between-group differences.

From these findings, what message can clinicians take to their patients? “Benefit is a much greater motivator, rather than the nebulous concept of risk,” said Dr. Ference. “So if we begin to crystallize and give an estimate of how much someone can benefit – either from adhering to a healthy lifestyle, with specific goals for LDL and blood pressure reductions, or from encouraging them to remain compliant with their therapies, achieving those corresponding goals – we can quantify their expected clinical benefit and encourage them to invest in their health over the long term.”

Dr. Ference said that the actual mechanism by which lipids and blood pressure are lowered matters less than the amount and duration of lowering: “These data are really agnostic as to the mechanism by which either blood pressure or LDL – or apo-B–containing lipoproteins generally – and blood pressure are reduced. It really suggests that whatever mechanism by which an individual person can most effectively lower their LDL and blood pressure, that’s the best one for that person, if they can maintain that over time.”

Dr. Ference reported financial relationships, including research contracts, consulting arrangements, receipt of royalties, and being an owner or stockholder of more than a dozen pharmaceutical companies. The study was funded by the United Kingdom’s National Institute of Health Research and Medical Research Council, and by the British Heart Foundation.

[email protected]

SOURCE: Ference B. et al. ESC Congress 2019, Hot Line Session 3.

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.

Bruce Jancin/MDedge News

It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”

The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.

Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).

The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.

The i3C analysis also demonstrated that exposure to cardiovascular risk factors in childhood has an adverse effect above and beyond that seen when the same risk factors are present only in adulthood. For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.

The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.

“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”

Clinical and policy implications

Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”

From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.

That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.

“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.

Bruce Jancin/MDedge News

In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”

“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.

“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.

What’s the best way forward?

“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”

He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.

Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.

“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.

The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.

[email protected]

PARIS – Though cardiovascular disease still accounts for 40% of deaths around the world, cancer is eclipsing cardiovascular disease as a cause of mortality in high income nations, according to new data from a global prospective study.

“Cancer deaths are becoming more frequent not because the rates of death from cancer are going up, but because we have decreased the deaths from cardiovascular disease,” said the study’s senior author, Salim Yusuf, MD, at the annual congress of the European Society of Cardiology.

A striking pattern emerged when cause of death was stratified by country income level, said fellow investigator Darryl P. Leong, MBBS, in presenting data regarding shifting global mortality patterns. Fully 55% of deaths in high-income nations were caused by cancer, compared with 30% in middle-income countries and 15% in low-income countries. In high-income countries, by contrast, cardiovascular disease (CVD) was the cause of death 23% of the time, while that figure was 42% and 43% for middle- and low-income countries, respectively.

Looking at the data slightly differently, the ratio of cardiovascular deaths to cancer deaths for high-income countries is 0.4; for middle-income countries, the ratio is 1.3, and “One is threefold more likely to die from cardiovascular disease as from cancer” in low-income countries, said Dr. Leong. Although the United States is not included in the PURE study, “recent data shows that some states in the U.S. also have higher cancer mortality than cardiovascular disease. This is a success story,” said Dr. Yusuf, since the shift is largely attributable to decreased mortality from CVD.

Dr. Leong and Dr. Yusuf each presented results from the PURE (Prospective Urban Rural Epidemiology) study, which has enrolled a total of 202,000 individuals from 27 countries on every inhabited continent but Australia. Follow-up data are available for 167,000 individuals in 21 countries. Canada, Russia, China, India, Brazil, and Chile are among the most populous national that are included. Their findings were published simultaneously in the Lancet with the congress presentations (2019 Sep 3; doi: 10.1016/S0140-6736(19)32008-2 and doi: 10.1016/S0140-6736(19)32007-0).

The INTERHEART risk score, an integrated cardiovascular risk score that uses non-laboratory values such as age, smoking status, family history, and comorbidities, was calculated for all participants. “We observed that the highest predicted cardiovascular risk is in high-income countries, and the lowest, in low-income countries,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Over the study period, 11,307 deaths occurred. Over 9,000 incident cardiovascular events were observed, as were over 5,000 new cancers.

“We have some interesting observations from these data,” said Dr. Leong. “Firstly, there is a gradient in the cardiovascular disease rates, moving from lowest in high-income countries – despite the fact that their INTERHEART risk score was highest – through to highest incident cardiovascular disease in low-income countries, despite their INTERHEART risk score being lowest.” This difference, said Dr. Leong, was driven by higher myocardial infarction rates in low-income countries and higher stroke rates in middle-income countries, when compared to high-income countries.

Once a participant was subject to one of the incident diseases, though, the patterns shifted. For CVD, cancer, chronic obstructive pulmonary disease, pneumonia, and injury, the likelihood of death within 1 year was highest in low-income countries – markedly higher, in the case of CVD. For all conditions, the one-year case-fatality rate after the occurrence of an incident disease was lowest in high-income countries.

“So we are seeing a new transition,” said Dr. Yusuf, the executive director of the Population Health Research Institute and Distinguished University Professor of Medicine, McMaster University, both in Hamilton, Ont. “The old transition was infectious diseases giving way to noncommunicable diseases. Now we are seeing a transition within noncommunicable diseases: In rich countries, cardiovascular disease is going down, perhaps due to better prevention, but I think even more importantly, due to better treatments.

“I want to hasten to add that the difference in risk between high-, middle-, and low-income countries in cardiovascular disease is not due to risk factors,” he went on. “Risk factors, if anything, are lower in the poor countries, compared to the higher-income countries.”

The shift away from cardiovascular disease mortality toward cancer mortality is also occurring in some countries that are in the upper tier of middle-income nations, including Chile, Argentina, Turkey, and Poland, said Dr. Yusuf, who presented data regarding the relative contributions of risk factors to cardiovascular disease and mortality.

Risk factors for cardiovascular disease in the PURE study were expressed by a measure called the population attributable fraction (PAF) that captures both the hazard ratio for a particular risk factor and the prevalence of the risk factor, explained Dr. Yusuf. “Hypertension, by far, was the biggest risk factor of cardiovascular disease globally,” he added, noting that the PAF for hypertension was over 20%. Hypertension far outstripped the next most significant risk factor, high non-HDL cholesterol, which had a PAF of less than 10%.

“This was a big surprise to us: Household pollution was a big factor,” said Dr. Yusuf, who later added that particulate matter from cooking, particularly with solid fuels such as wood or charcoal, was likely the source of much household air pollution, “a big problem in middle- and low-income countries.”

Tobacco usage is decreasing, as is its contribution to cardiovascular deaths, but other commonly cited culprits for cardiovascular disease were not significant contributors to cardiovascular disease in the PURE population.

“Abdominal obesity, and not BMI” contributes to cardiovascular risk. “BMI is not a good indicator of risk,” said Dr. Yusuf in a video interview. These results were presented separately at the congress.

“Grip strength is important; in fact, it is more important than low physical activity. People have focused on physical activity – how much you do. But strength seems to be more important…We haven’t focused on the importance of strength in the past.”

“Salt doesn’t figure in at all; salt has been exaggerated as a risk factor,” said Dr. Yusuf. “Diet needs to be rethought,” and conventional thinking challenged, he added, noting that consumption of full-fat dairy, nuts, and a moderate amount of meat all were protective among the PURE cohort.

Looking next at factors contributing to mortality in the global PURE population, low educational level had the highest attributable fraction of mortality of any single risk factor, at about 12%. “This has been ignored,” said Dr. Yusuf. “In most epidemiological studies, it’s been used as a covariate, or a stratifier,” rather than addressing low education itself as a risk factor, he said.

Tobacco use, low grip strength, and poor diet all had attributable fractions of just over 10%, said Dr. Yusuf, again noting that it wasn’t fat or meat consumption that made for the riskiest diet.

Overall, metabolic risk factors accounted for the largest fraction of risk of cardiovascular disease in the PURE population, with behavioral risk factors such as alcohol and tobacco use coming next. This held true across all income categories. However, in higher income nations where environmental factors and household air pollution are lower contributors to cardiovascular disease, metabolic and behavioral risk factors contributed more to cardiovascular disease risk.

Global differences in cardiovascular disease rates, stressed Dr. Yusuf, are not primarily attributable to metabolic risk factors. “The [World Health Organization] has focused on risk factors and has not focused on improved health care. Health care matters, and it matters in a big way.”

Adults aged 35-70 were recruited from 4 high-, 12 middle- and 5 low-income countries for PURE, and followed for a median 9.5 years. Cardiovascular disease and other health events salient to the study were documented both through direct contact and administrative record review, said Dr. Leong, and data about cardiovascular events and vital status were known for well over 90% of study participants.

Slightly less than half of participants were male, and over 108,000 participants were from middle income countries.

The PURE study was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Ontaario Ministry of Health and Long-Term Care, Astra Zeneca, Boehringer Ingelheim, Sanofi-Aentis, Servier Laboratories, and Glaxo Smith Kline. The study also received additional support in individual participating countries. Dr. Yusuf and Dr. Leon reported that they had no relevant conflicts of interest.

[email protected]

PARIS – Though cardiovascular disease still accounts for 40% of deaths around the world, cancer is eclipsing cardiovascular disease as a cause of mortality in high income nations, according to new data from a global prospective study.

“Cancer deaths are becoming more frequent not because the rates of death from cancer are going up, but because we have decreased the deaths from cardiovascular disease,” said the study’s senior author, Salim Yusuf, MD, at the annual congress of the European Society of Cardiology.

A striking pattern emerged when cause of death was stratified by country income level, said fellow investigator Darryl P. Leong, MBBS, in presenting data regarding shifting global mortality patterns. Fully 55% of deaths in high-income nations were caused by cancer, compared with 30% in middle-income countries and 15% in low-income countries. In high-income countries, by contrast, cardiovascular disease (CVD) was the cause of death 23% of the time, while that figure was 42% and 43% for middle- and low-income countries, respectively.

Looking at the data slightly differently, the ratio of cardiovascular deaths to cancer deaths for high-income countries is 0.4; for middle-income countries, the ratio is 1.3, and “One is threefold more likely to die from cardiovascular disease as from cancer” in low-income countries, said Dr. Leong. Although the United States is not included in the PURE study, “recent data shows that some states in the U.S. also have higher cancer mortality than cardiovascular disease. This is a success story,” said Dr. Yusuf, since the shift is largely attributable to decreased mortality from CVD.

Dr. Leong and Dr. Yusuf each presented results from the PURE (Prospective Urban Rural Epidemiology) study, which has enrolled a total of 202,000 individuals from 27 countries on every inhabited continent but Australia. Follow-up data are available for 167,000 individuals in 21 countries. Canada, Russia, China, India, Brazil, and Chile are among the most populous national that are included. Their findings were published simultaneously in the Lancet with the congress presentations (2019 Sep 3; doi: 10.1016/S0140-6736(19)32008-2 and doi: 10.1016/S0140-6736(19)32007-0).

The INTERHEART risk score, an integrated cardiovascular risk score that uses non-laboratory values such as age, smoking status, family history, and comorbidities, was calculated for all participants. “We observed that the highest predicted cardiovascular risk is in high-income countries, and the lowest, in low-income countries,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Over the study period, 11,307 deaths occurred. Over 9,000 incident cardiovascular events were observed, as were over 5,000 new cancers.

“We have some interesting observations from these data,” said Dr. Leong. “Firstly, there is a gradient in the cardiovascular disease rates, moving from lowest in high-income countries – despite the fact that their INTERHEART risk score was highest – through to highest incident cardiovascular disease in low-income countries, despite their INTERHEART risk score being lowest.” This difference, said Dr. Leong, was driven by higher myocardial infarction rates in low-income countries and higher stroke rates in middle-income countries, when compared to high-income countries.

Once a participant was subject to one of the incident diseases, though, the patterns shifted. For CVD, cancer, chronic obstructive pulmonary disease, pneumonia, and injury, the likelihood of death within 1 year was highest in low-income countries – markedly higher, in the case of CVD. For all conditions, the one-year case-fatality rate after the occurrence of an incident disease was lowest in high-income countries.

“So we are seeing a new transition,” said Dr. Yusuf, the executive director of the Population Health Research Institute and Distinguished University Professor of Medicine, McMaster University, both in Hamilton, Ont. “The old transition was infectious diseases giving way to noncommunicable diseases. Now we are seeing a transition within noncommunicable diseases: In rich countries, cardiovascular disease is going down, perhaps due to better prevention, but I think even more importantly, due to better treatments.

“I want to hasten to add that the difference in risk between high-, middle-, and low-income countries in cardiovascular disease is not due to risk factors,” he went on. “Risk factors, if anything, are lower in the poor countries, compared to the higher-income countries.”

The shift away from cardiovascular disease mortality toward cancer mortality is also occurring in some countries that are in the upper tier of middle-income nations, including Chile, Argentina, Turkey, and Poland, said Dr. Yusuf, who presented data regarding the relative contributions of risk factors to cardiovascular disease and mortality.

Risk factors for cardiovascular disease in the PURE study were expressed by a measure called the population attributable fraction (PAF) that captures both the hazard ratio for a particular risk factor and the prevalence of the risk factor, explained Dr. Yusuf. “Hypertension, by far, was the biggest risk factor of cardiovascular disease globally,” he added, noting that the PAF for hypertension was over 20%. Hypertension far outstripped the next most significant risk factor, high non-HDL cholesterol, which had a PAF of less than 10%.

“This was a big surprise to us: Household pollution was a big factor,” said Dr. Yusuf, who later added that particulate matter from cooking, particularly with solid fuels such as wood or charcoal, was likely the source of much household air pollution, “a big problem in middle- and low-income countries.”

Tobacco usage is decreasing, as is its contribution to cardiovascular deaths, but other commonly cited culprits for cardiovascular disease were not significant contributors to cardiovascular disease in the PURE population.

“Abdominal obesity, and not BMI” contributes to cardiovascular risk. “BMI is not a good indicator of risk,” said Dr. Yusuf in a video interview. These results were presented separately at the congress.

“Grip strength is important; in fact, it is more important than low physical activity. People have focused on physical activity – how much you do. But strength seems to be more important…We haven’t focused on the importance of strength in the past.”

“Salt doesn’t figure in at all; salt has been exaggerated as a risk factor,” said Dr. Yusuf. “Diet needs to be rethought,” and conventional thinking challenged, he added, noting that consumption of full-fat dairy, nuts, and a moderate amount of meat all were protective among the PURE cohort.

Looking next at factors contributing to mortality in the global PURE population, low educational level had the highest attributable fraction of mortality of any single risk factor, at about 12%. “This has been ignored,” said Dr. Yusuf. “In most epidemiological studies, it’s been used as a covariate, or a stratifier,” rather than addressing low education itself as a risk factor, he said.

Tobacco use, low grip strength, and poor diet all had attributable fractions of just over 10%, said Dr. Yusuf, again noting that it wasn’t fat or meat consumption that made for the riskiest diet.

Overall, metabolic risk factors accounted for the largest fraction of risk of cardiovascular disease in the PURE population, with behavioral risk factors such as alcohol and tobacco use coming next. This held true across all income categories. However, in higher income nations where environmental factors and household air pollution are lower contributors to cardiovascular disease, metabolic and behavioral risk factors contributed more to cardiovascular disease risk.

Global differences in cardiovascular disease rates, stressed Dr. Yusuf, are not primarily attributable to metabolic risk factors. “The [World Health Organization] has focused on risk factors and has not focused on improved health care. Health care matters, and it matters in a big way.”

Adults aged 35-70 were recruited from 4 high-, 12 middle- and 5 low-income countries for PURE, and followed for a median 9.5 years. Cardiovascular disease and other health events salient to the study were documented both through direct contact and administrative record review, said Dr. Leong, and data about cardiovascular events and vital status were known for well over 90% of study participants.

Slightly less than half of participants were male, and over 108,000 participants were from middle income countries.

The PURE study was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Ontaario Ministry of Health and Long-Term Care, Astra Zeneca, Boehringer Ingelheim, Sanofi-Aentis, Servier Laboratories, and Glaxo Smith Kline. The study also received additional support in individual participating countries. Dr. Yusuf and Dr. Leon reported that they had no relevant conflicts of interest.

[email protected]

PARIS – Though cardiovascular disease still accounts for 40% of deaths around the world, cancer is eclipsing cardiovascular disease as a cause of mortality in high income nations, according to new data from a global prospective study.

“Cancer deaths are becoming more frequent not because the rates of death from cancer are going up, but because we have decreased the deaths from cardiovascular disease,” said the study’s senior author, Salim Yusuf, MD, at the annual congress of the European Society of Cardiology.

A striking pattern emerged when cause of death was stratified by country income level, said fellow investigator Darryl P. Leong, MBBS, in presenting data regarding shifting global mortality patterns. Fully 55% of deaths in high-income nations were caused by cancer, compared with 30% in middle-income countries and 15% in low-income countries. In high-income countries, by contrast, cardiovascular disease (CVD) was the cause of death 23% of the time, while that figure was 42% and 43% for middle- and low-income countries, respectively.

Looking at the data slightly differently, the ratio of cardiovascular deaths to cancer deaths for high-income countries is 0.4; for middle-income countries, the ratio is 1.3, and “One is threefold more likely to die from cardiovascular disease as from cancer” in low-income countries, said Dr. Leong. Although the United States is not included in the PURE study, “recent data shows that some states in the U.S. also have higher cancer mortality than cardiovascular disease. This is a success story,” said Dr. Yusuf, since the shift is largely attributable to decreased mortality from CVD.

Dr. Leong and Dr. Yusuf each presented results from the PURE (Prospective Urban Rural Epidemiology) study, which has enrolled a total of 202,000 individuals from 27 countries on every inhabited continent but Australia. Follow-up data are available for 167,000 individuals in 21 countries. Canada, Russia, China, India, Brazil, and Chile are among the most populous national that are included. Their findings were published simultaneously in the Lancet with the congress presentations (2019 Sep 3; doi: 10.1016/S0140-6736(19)32008-2 and doi: 10.1016/S0140-6736(19)32007-0).

The INTERHEART risk score, an integrated cardiovascular risk score that uses non-laboratory values such as age, smoking status, family history, and comorbidities, was calculated for all participants. “We observed that the highest predicted cardiovascular risk is in high-income countries, and the lowest, in low-income countries,” said Dr. Leong, a cardiologist at McMaster University and the Population Health Research Institute, both in Hamilton, Ont.

Over the study period, 11,307 deaths occurred. Over 9,000 incident cardiovascular events were observed, as were over 5,000 new cancers.

“We have some interesting observations from these data,” said Dr. Leong. “Firstly, there is a gradient in the cardiovascular disease rates, moving from lowest in high-income countries – despite the fact that their INTERHEART risk score was highest – through to highest incident cardiovascular disease in low-income countries, despite their INTERHEART risk score being lowest.” This difference, said Dr. Leong, was driven by higher myocardial infarction rates in low-income countries and higher stroke rates in middle-income countries, when compared to high-income countries.

Once a participant was subject to one of the incident diseases, though, the patterns shifted. For CVD, cancer, chronic obstructive pulmonary disease, pneumonia, and injury, the likelihood of death within 1 year was highest in low-income countries – markedly higher, in the case of CVD. For all conditions, the one-year case-fatality rate after the occurrence of an incident disease was lowest in high-income countries.

“So we are seeing a new transition,” said Dr. Yusuf, the executive director of the Population Health Research Institute and Distinguished University Professor of Medicine, McMaster University, both in Hamilton, Ont. “The old transition was infectious diseases giving way to noncommunicable diseases. Now we are seeing a transition within noncommunicable diseases: In rich countries, cardiovascular disease is going down, perhaps due to better prevention, but I think even more importantly, due to better treatments.

“I want to hasten to add that the difference in risk between high-, middle-, and low-income countries in cardiovascular disease is not due to risk factors,” he went on. “Risk factors, if anything, are lower in the poor countries, compared to the higher-income countries.”

The shift away from cardiovascular disease mortality toward cancer mortality is also occurring in some countries that are in the upper tier of middle-income nations, including Chile, Argentina, Turkey, and Poland, said Dr. Yusuf, who presented data regarding the relative contributions of risk factors to cardiovascular disease and mortality.

Risk factors for cardiovascular disease in the PURE study were expressed by a measure called the population attributable fraction (PAF) that captures both the hazard ratio for a particular risk factor and the prevalence of the risk factor, explained Dr. Yusuf. “Hypertension, by far, was the biggest risk factor of cardiovascular disease globally,” he added, noting that the PAF for hypertension was over 20%. Hypertension far outstripped the next most significant risk factor, high non-HDL cholesterol, which had a PAF of less than 10%.

“This was a big surprise to us: Household pollution was a big factor,” said Dr. Yusuf, who later added that particulate matter from cooking, particularly with solid fuels such as wood or charcoal, was likely the source of much household air pollution, “a big problem in middle- and low-income countries.”

Tobacco usage is decreasing, as is its contribution to cardiovascular deaths, but other commonly cited culprits for cardiovascular disease were not significant contributors to cardiovascular disease in the PURE population.

“Abdominal obesity, and not BMI” contributes to cardiovascular risk. “BMI is not a good indicator of risk,” said Dr. Yusuf in a video interview. These results were presented separately at the congress.

“Grip strength is important; in fact, it is more important than low physical activity. People have focused on physical activity – how much you do. But strength seems to be more important…We haven’t focused on the importance of strength in the past.”

“Salt doesn’t figure in at all; salt has been exaggerated as a risk factor,” said Dr. Yusuf. “Diet needs to be rethought,” and conventional thinking challenged, he added, noting that consumption of full-fat dairy, nuts, and a moderate amount of meat all were protective among the PURE cohort.

Looking next at factors contributing to mortality in the global PURE population, low educational level had the highest attributable fraction of mortality of any single risk factor, at about 12%. “This has been ignored,” said Dr. Yusuf. “In most epidemiological studies, it’s been used as a covariate, or a stratifier,” rather than addressing low education itself as a risk factor, he said.

Tobacco use, low grip strength, and poor diet all had attributable fractions of just over 10%, said Dr. Yusuf, again noting that it wasn’t fat or meat consumption that made for the riskiest diet.

Overall, metabolic risk factors accounted for the largest fraction of risk of cardiovascular disease in the PURE population, with behavioral risk factors such as alcohol and tobacco use coming next. This held true across all income categories. However, in higher income nations where environmental factors and household air pollution are lower contributors to cardiovascular disease, metabolic and behavioral risk factors contributed more to cardiovascular disease risk.

Global differences in cardiovascular disease rates, stressed Dr. Yusuf, are not primarily attributable to metabolic risk factors. “The [World Health Organization] has focused on risk factors and has not focused on improved health care. Health care matters, and it matters in a big way.”

Adults aged 35-70 were recruited from 4 high-, 12 middle- and 5 low-income countries for PURE, and followed for a median 9.5 years. Cardiovascular disease and other health events salient to the study were documented both through direct contact and administrative record review, said Dr. Leong, and data about cardiovascular events and vital status were known for well over 90% of study participants.

Slightly less than half of participants were male, and over 108,000 participants were from middle income countries.

The PURE study was supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Ontaario Ministry of Health and Long-Term Care, Astra Zeneca, Boehringer Ingelheim, Sanofi-Aentis, Servier Laboratories, and Glaxo Smith Kline. The study also received additional support in individual participating countries. Dr. Yusuf and Dr. Leon reported that they had no relevant conflicts of interest.

[email protected]

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.

Statin use for a minimum of 3 months was significantly associated with an increased risk of skin and soft tissue infections (SSTIs), according to a sequence symmetry analysis of prescription claims over a 10-year period reported in the British Journal of Clinical Pharmacology.

In the study, statin use for as little as 91 days was linked with elevated risks of SSTIs and diabetes. However, the increased risk of infection was seen in individuals who did and did not develop diabetes, wrote Humphrey Ko, of the school of pharmacy and biomedical sciences, Curtin University, Perth, Australia, and colleagues.

The current literature on the impact of statins on SSTIs is conflicted, they noted. Previous research shows that statins “may reduce the risk of community-acquired [Staphylococcus aureus] bacteremia and exert antibacterial effects against S. aureus,” and therefore may have potential for reducing SSTI risk “or evolve into promising novel treatments for SSTIs,” the researchers said; they noted, however, that other data show that statins may induce new-onset diabetes.

They examined prescription claims (for statins, antidiabetic medications, and antistaphylococcal antibiotics) from 2001 to 2011 from the Australian Department of Veterans’ Affairs that included more than 228,000 veterans, war widows, and widowers. Prescriptions for antistaphylococcal antibiotics were used as a marker of SSTIs.

Overall, statins were significantly associated with an increased risk of SSTIs at 91 days (adjusted sequence ratio, 1.40). The risk of SSTIs from statin use was similar at 182 (ASR, 1.41) and 365 days (ASR, 1.40). In this case, the ASRs represent the incidence rate ratios of prescribing antibiotics in statin-exposed versus statin-nonexposed person-time.

Statins were associated with a significantly increased risk of new onset diabetes, but the SSTI risk was not significantly different between statin users with and without diabetes. Statin users who did not have diabetes had significant SSTI risks at 91, 182, and 365 days (ASR, 1.39, 1.41, and 1.37, respectively) and statin users with diabetes had similarly significant risks of SSTIs (ASR,1.43, 1.42, and 1.49, respectively).

In addition, socioeconomic status appeared to have no significant effect on the relationship between statin use, SSTIs, and diabetes, the researchers noted.

The findings were limited by several factors including the inability to account for patient compliance in taking the medications, a lack of dosage data to determine the impact of dosage on outcomes, and potential confounding by the presence of diabetes, they said. However, the results suggest that “it would seem prudent for clinicians to monitor blood glucose levels of statin users who are predisposed to diabetes, and be mindful of possible increased SSTI risks in such patients,” they concluded. Statins, they added, “may increase SSTI risk via direct or indirect mechanisms.”

More clinical trials are needed to confirm the mechanisms, and “to ascertain the effect of statins on gut dysbiosis, impaired bile acid metabolism, vitamin D levels, and cholesterol inhibition on skin function,” they wrote.

The study was supported in part by the Australian Government Research Training Program Scholarship, the Curtin Health Innovation Research Institute Biosciences Research Precinct Core Facility, and the School of Pharmacy and Biomedical Sciences (Curtin University). The researchers had no financial conflicts to disclose.

SOURCE: Ko H et al. Br J Clin Pharmacol. 2019 Oct 9. doi: 10.1111/bcp.14077.