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Clot retrieval devices approved for initial ischemic stroke treatment
Two Trevo clot retrieval devices can now be marketed as an initial therapy to reduce paralysis from strokes that are caused by blood clots, according to a press release from the Food and Drug Administration.
Previously, the only first-line treatment approved for acute ischemic stroke was tissue plasminogen activator (TPA) delivered intravenously. The FDA approved Trevo devices based on a clinical trial in which 29% of patients treated with the Trevo device combined with TPA and medical management of blood pressure and disability symptoms were shown to be functionally independent 3 months after their stroke, compared with only 19% of patients treated with TPA plus medical management alone.
The Trevo devices are approved for usage within 6 hours of symptom onset and only following treatment with TPA, which should be administered within 3 hours of stroke onset. Associated risks with Trevo device usage include failure to retrieve the blood clot, device malfunctions including breakage and navigation difficulties, potential damage of blood vessels, and the chance of perforation or hemorrhage.
The Trevo device was first approved by the FDA in 2012 to remove blood clots in order to restore blood flow in stroke patients who could not receive TPA or for those patients who did not respond to TPA therapy. The current approval expands the devices’ indication to a broader group of patients, according to the release.
“This is the first time FDA has allowed the use of these devices alongside TPA, which has the potential to help further reduce the devastating disabilities associated with strokes compared to the use of TPA alone. Now health care providers and their patients have another tool for treating stroke and potentially preventing long-term disability,” Carlos Peña, PhD, director of the division of neurological and physical medicine devices at the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
Two Trevo clot retrieval devices can now be marketed as an initial therapy to reduce paralysis from strokes that are caused by blood clots, according to a press release from the Food and Drug Administration.
Previously, the only first-line treatment approved for acute ischemic stroke was tissue plasminogen activator (TPA) delivered intravenously. The FDA approved Trevo devices based on a clinical trial in which 29% of patients treated with the Trevo device combined with TPA and medical management of blood pressure and disability symptoms were shown to be functionally independent 3 months after their stroke, compared with only 19% of patients treated with TPA plus medical management alone.
The Trevo devices are approved for usage within 6 hours of symptom onset and only following treatment with TPA, which should be administered within 3 hours of stroke onset. Associated risks with Trevo device usage include failure to retrieve the blood clot, device malfunctions including breakage and navigation difficulties, potential damage of blood vessels, and the chance of perforation or hemorrhage.
The Trevo device was first approved by the FDA in 2012 to remove blood clots in order to restore blood flow in stroke patients who could not receive TPA or for those patients who did not respond to TPA therapy. The current approval expands the devices’ indication to a broader group of patients, according to the release.
“This is the first time FDA has allowed the use of these devices alongside TPA, which has the potential to help further reduce the devastating disabilities associated with strokes compared to the use of TPA alone. Now health care providers and their patients have another tool for treating stroke and potentially preventing long-term disability,” Carlos Peña, PhD, director of the division of neurological and physical medicine devices at the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
Two Trevo clot retrieval devices can now be marketed as an initial therapy to reduce paralysis from strokes that are caused by blood clots, according to a press release from the Food and Drug Administration.
Previously, the only first-line treatment approved for acute ischemic stroke was tissue plasminogen activator (TPA) delivered intravenously. The FDA approved Trevo devices based on a clinical trial in which 29% of patients treated with the Trevo device combined with TPA and medical management of blood pressure and disability symptoms were shown to be functionally independent 3 months after their stroke, compared with only 19% of patients treated with TPA plus medical management alone.
The Trevo devices are approved for usage within 6 hours of symptom onset and only following treatment with TPA, which should be administered within 3 hours of stroke onset. Associated risks with Trevo device usage include failure to retrieve the blood clot, device malfunctions including breakage and navigation difficulties, potential damage of blood vessels, and the chance of perforation or hemorrhage.
The Trevo device was first approved by the FDA in 2012 to remove blood clots in order to restore blood flow in stroke patients who could not receive TPA or for those patients who did not respond to TPA therapy. The current approval expands the devices’ indication to a broader group of patients, according to the release.
“This is the first time FDA has allowed the use of these devices alongside TPA, which has the potential to help further reduce the devastating disabilities associated with strokes compared to the use of TPA alone. Now health care providers and their patients have another tool for treating stroke and potentially preventing long-term disability,” Carlos Peña, PhD, director of the division of neurological and physical medicine devices at the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
Stroke risk rises quickly in recent-onset atrial fib
CHICAGO – The stroke risk in patients with recent-onset atrial fibrillation is similar to that of patients with longer-standing atrial fibrillation, according to a new secondary analysis of the landmark ARISTOTLE trial.
“Our key message is that patients with recent-onset atrial fibrillation had a similar risk of stroke but higher mortality than patients with remotely diagnosed atrial fibrillation, suggesting that patients with recently diagnosed atrial fibrillation are not at low risk and therefore warrant stroke prevention strategies,” Dr. Patricia O. Guimaraes said in presenting the findings at the annual meeting of the American College of Cardiology.
“Sometimes we as physicians hesitate in beginning oral anticoagulation therapy for patients that we just diagnosed. And of course patients are often afraid of anticoagulation therapy. But once they present with atrial fibrillation they are already at risk, and that’s why we need to anticoagulate them promptly,” added Dr. Guimaraes of the Duke Clinical Research Institute in Durham, N.C.
The benefits of apixaban (Eliquis) over warfarin seen in the overall randomized ARISTOTLE trial (N Engl J Med. 2011; 365:981-92) were preserved in the recent-onset subset of the atrial fibrillation (AF) study population, she noted.
The rationale for this new post hoc analysis of ARISTOTLE is that virtually all of the evidence supporting anticoagulation for stroke prevention in AF is based on studies conducted in patients with permanent, persistent, or long-standing paroxysmal AF. Much less is known about stroke risk and the benefits of anticoagulation in patients with recent-onset AF, Dr. Guimaraes explained.
The 1,899 ARISTOTLE participants with AF onset within 30 days prior to enrollment comprised 10.5% of the total study population, all of whom had AF and at least one other stroke risk factor. The recent-onset subgroup was the same age as the 16,241 subjects in this analysis who had longer-standing AF, but the recent-onset group included a higher proportion of women, had a lower prevalence of CAD, and their cardiovascular risk factor profile differed from that of the remote-onset AF group.
The composite endpoint of stroke, systemic embolism, major bleeding, or all-cause mortality occurred at a rate of 8.69%/year in the recent-onset AF group, compared with 6.43%/year in the remote-onset group. However, in a multivariate regression analysis adjusted for potential confounders, the only significant differences in outcome between the two groups were in all-cause mortality – 5.15%/year in the recent-onset group, 3.15% in the remote-onset AF patients – and in the composite of stroke, systemic embolism, or all-cause mortality, which had an incidence of 6.46%/year in the recent-onset group, compared with 4.57%/year in remote-onset patients.
Turning to the impact of apixaban, Dr. Guimaraes noted that, as previously reported in the overall study, the primary endpoint of stroke or systemic embolism occurred in the apixaban group at a rate of 1.27%/year, compared with 1.6%/year with warfarin, for a 21% relative risk reduction in favor of the newer agent. She and her coinvestigators determined that in the remote-onset AF subgroup the relative risk reduction was 20%, while in the recent-onset subgroup the size of the effect was similar at 22%.
The composite safety endpoint of major or clinically relevant bleeding occurred in the remote-onset patients at a rate of 3.97%/year with apixaban versus 5.97%/year with warfarin, for a 33% relative risk reduction favoring the novel agent. In the recent-onset group, the rates were 5.04%/year with apixaban, compared with 6.4%/year with warfarin, for a 22% relative risk reduction.
Dr. Guimaraes observed an important limitation of this post hoc analysis is that the remote-onset AF group may have been selected for improved survival, since they didn’t die in the first 30 days after diagnosis.
Session co-chair Dr. Brian Olshansky commented that this analysis, which highlights the risks of recent-onset AF, argues for a strategy whereby a patient who presents to the ED with new-onset AF should get sent home on apixaban rather than being hospitalized for several days in order to be stabilized on warfarin.
“With recent-onset atrial fibrillation it’s going to take you several days to get anticoagulated with warfarin, whereas you’re immediately anticoagulated with apixaban,” said Dr. Olshansky, emeritus professor of internal medicine at the University of Iowa, Iowa City.
The ARISTOTLE trial was supported by Bristol-Myers Squibb and Pfizer. Dr. Guimaraes reported having no financial conflicts of interest.
CHICAGO – The stroke risk in patients with recent-onset atrial fibrillation is similar to that of patients with longer-standing atrial fibrillation, according to a new secondary analysis of the landmark ARISTOTLE trial.
“Our key message is that patients with recent-onset atrial fibrillation had a similar risk of stroke but higher mortality than patients with remotely diagnosed atrial fibrillation, suggesting that patients with recently diagnosed atrial fibrillation are not at low risk and therefore warrant stroke prevention strategies,” Dr. Patricia O. Guimaraes said in presenting the findings at the annual meeting of the American College of Cardiology.
“Sometimes we as physicians hesitate in beginning oral anticoagulation therapy for patients that we just diagnosed. And of course patients are often afraid of anticoagulation therapy. But once they present with atrial fibrillation they are already at risk, and that’s why we need to anticoagulate them promptly,” added Dr. Guimaraes of the Duke Clinical Research Institute in Durham, N.C.
The benefits of apixaban (Eliquis) over warfarin seen in the overall randomized ARISTOTLE trial (N Engl J Med. 2011; 365:981-92) were preserved in the recent-onset subset of the atrial fibrillation (AF) study population, she noted.
The rationale for this new post hoc analysis of ARISTOTLE is that virtually all of the evidence supporting anticoagulation for stroke prevention in AF is based on studies conducted in patients with permanent, persistent, or long-standing paroxysmal AF. Much less is known about stroke risk and the benefits of anticoagulation in patients with recent-onset AF, Dr. Guimaraes explained.
The 1,899 ARISTOTLE participants with AF onset within 30 days prior to enrollment comprised 10.5% of the total study population, all of whom had AF and at least one other stroke risk factor. The recent-onset subgroup was the same age as the 16,241 subjects in this analysis who had longer-standing AF, but the recent-onset group included a higher proportion of women, had a lower prevalence of CAD, and their cardiovascular risk factor profile differed from that of the remote-onset AF group.
The composite endpoint of stroke, systemic embolism, major bleeding, or all-cause mortality occurred at a rate of 8.69%/year in the recent-onset AF group, compared with 6.43%/year in the remote-onset group. However, in a multivariate regression analysis adjusted for potential confounders, the only significant differences in outcome between the two groups were in all-cause mortality – 5.15%/year in the recent-onset group, 3.15% in the remote-onset AF patients – and in the composite of stroke, systemic embolism, or all-cause mortality, which had an incidence of 6.46%/year in the recent-onset group, compared with 4.57%/year in remote-onset patients.
Turning to the impact of apixaban, Dr. Guimaraes noted that, as previously reported in the overall study, the primary endpoint of stroke or systemic embolism occurred in the apixaban group at a rate of 1.27%/year, compared with 1.6%/year with warfarin, for a 21% relative risk reduction in favor of the newer agent. She and her coinvestigators determined that in the remote-onset AF subgroup the relative risk reduction was 20%, while in the recent-onset subgroup the size of the effect was similar at 22%.
The composite safety endpoint of major or clinically relevant bleeding occurred in the remote-onset patients at a rate of 3.97%/year with apixaban versus 5.97%/year with warfarin, for a 33% relative risk reduction favoring the novel agent. In the recent-onset group, the rates were 5.04%/year with apixaban, compared with 6.4%/year with warfarin, for a 22% relative risk reduction.
Dr. Guimaraes observed an important limitation of this post hoc analysis is that the remote-onset AF group may have been selected for improved survival, since they didn’t die in the first 30 days after diagnosis.
Session co-chair Dr. Brian Olshansky commented that this analysis, which highlights the risks of recent-onset AF, argues for a strategy whereby a patient who presents to the ED with new-onset AF should get sent home on apixaban rather than being hospitalized for several days in order to be stabilized on warfarin.
“With recent-onset atrial fibrillation it’s going to take you several days to get anticoagulated with warfarin, whereas you’re immediately anticoagulated with apixaban,” said Dr. Olshansky, emeritus professor of internal medicine at the University of Iowa, Iowa City.
The ARISTOTLE trial was supported by Bristol-Myers Squibb and Pfizer. Dr. Guimaraes reported having no financial conflicts of interest.
CHICAGO – The stroke risk in patients with recent-onset atrial fibrillation is similar to that of patients with longer-standing atrial fibrillation, according to a new secondary analysis of the landmark ARISTOTLE trial.
“Our key message is that patients with recent-onset atrial fibrillation had a similar risk of stroke but higher mortality than patients with remotely diagnosed atrial fibrillation, suggesting that patients with recently diagnosed atrial fibrillation are not at low risk and therefore warrant stroke prevention strategies,” Dr. Patricia O. Guimaraes said in presenting the findings at the annual meeting of the American College of Cardiology.
“Sometimes we as physicians hesitate in beginning oral anticoagulation therapy for patients that we just diagnosed. And of course patients are often afraid of anticoagulation therapy. But once they present with atrial fibrillation they are already at risk, and that’s why we need to anticoagulate them promptly,” added Dr. Guimaraes of the Duke Clinical Research Institute in Durham, N.C.
The benefits of apixaban (Eliquis) over warfarin seen in the overall randomized ARISTOTLE trial (N Engl J Med. 2011; 365:981-92) were preserved in the recent-onset subset of the atrial fibrillation (AF) study population, she noted.
The rationale for this new post hoc analysis of ARISTOTLE is that virtually all of the evidence supporting anticoagulation for stroke prevention in AF is based on studies conducted in patients with permanent, persistent, or long-standing paroxysmal AF. Much less is known about stroke risk and the benefits of anticoagulation in patients with recent-onset AF, Dr. Guimaraes explained.
The 1,899 ARISTOTLE participants with AF onset within 30 days prior to enrollment comprised 10.5% of the total study population, all of whom had AF and at least one other stroke risk factor. The recent-onset subgroup was the same age as the 16,241 subjects in this analysis who had longer-standing AF, but the recent-onset group included a higher proportion of women, had a lower prevalence of CAD, and their cardiovascular risk factor profile differed from that of the remote-onset AF group.
The composite endpoint of stroke, systemic embolism, major bleeding, or all-cause mortality occurred at a rate of 8.69%/year in the recent-onset AF group, compared with 6.43%/year in the remote-onset group. However, in a multivariate regression analysis adjusted for potential confounders, the only significant differences in outcome between the two groups were in all-cause mortality – 5.15%/year in the recent-onset group, 3.15% in the remote-onset AF patients – and in the composite of stroke, systemic embolism, or all-cause mortality, which had an incidence of 6.46%/year in the recent-onset group, compared with 4.57%/year in remote-onset patients.
Turning to the impact of apixaban, Dr. Guimaraes noted that, as previously reported in the overall study, the primary endpoint of stroke or systemic embolism occurred in the apixaban group at a rate of 1.27%/year, compared with 1.6%/year with warfarin, for a 21% relative risk reduction in favor of the newer agent. She and her coinvestigators determined that in the remote-onset AF subgroup the relative risk reduction was 20%, while in the recent-onset subgroup the size of the effect was similar at 22%.
The composite safety endpoint of major or clinically relevant bleeding occurred in the remote-onset patients at a rate of 3.97%/year with apixaban versus 5.97%/year with warfarin, for a 33% relative risk reduction favoring the novel agent. In the recent-onset group, the rates were 5.04%/year with apixaban, compared with 6.4%/year with warfarin, for a 22% relative risk reduction.
Dr. Guimaraes observed an important limitation of this post hoc analysis is that the remote-onset AF group may have been selected for improved survival, since they didn’t die in the first 30 days after diagnosis.
Session co-chair Dr. Brian Olshansky commented that this analysis, which highlights the risks of recent-onset AF, argues for a strategy whereby a patient who presents to the ED with new-onset AF should get sent home on apixaban rather than being hospitalized for several days in order to be stabilized on warfarin.
“With recent-onset atrial fibrillation it’s going to take you several days to get anticoagulated with warfarin, whereas you’re immediately anticoagulated with apixaban,” said Dr. Olshansky, emeritus professor of internal medicine at the University of Iowa, Iowa City.
The ARISTOTLE trial was supported by Bristol-Myers Squibb and Pfizer. Dr. Guimaraes reported having no financial conflicts of interest.
Key clinical point: Don’t delay starting oral anticoagulation in patients with recent-onset atrial fibrillation.
Major finding: All-cause mortality occurred at a rate of 5.15%/year in patients started on apixaban or warfarin within 30 days following diagnosis of atrial fibrillation, compared with 3.15%/year in those with longer-duration atrial fibrillation.
Data source: This was a secondary post hoc analysis of 18,140 participants in the randomized, double-blind, prospective ARISTOTLE trial of apixaban versus warfarin for stroke prevention.
Disclosures: The study presenter reported having no financial conflicts of interest.
Strong gender difference for stroke in diabetes patients with restless legs syndrome
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
AT ACC 16
Key clinical point: Diabetic women who have restless legs syndrome face a sharply elevated risk of stroke.
Major finding: Stroke occurred in 18.2% of diabetic women with restless legs syndrome, compared with 7% of men.
Data source: This retrospective cohort study included 385 patients with restless legs syndrome and 770 propensity-matched controls.
Disclosures: This study was conducted free of commercial support. The presenter reported having no financial conflicts.
Strong gender difference for stroke in diabetes patients with restless legs syndrome
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
CHICAGO – Stroke risk in diabetic women with restless legs syndrome (RLS) is triple that of diabetic men with the sensorimotor disease, Zoe Heis reported at the annual meeting of the American College of Cardiology.
The mechanism underlying this marked gender discrepancy in risk requires further investigation, as does the highly practical question of whether improved diabetic control can reduce the stroke risk, said Ms. Heis of the Center for Integrative Research on Cardiovascular Aging at Aurora Health Care in Milwaukee.
She presented a retrospective cohort study of 385 patients diagnosed with RLS during 2011-2013 at a community sleep center using the International RLS Study Group criteria. Along with 770 propensity-matched controls, they were followed until mid-2015. At baseline, 40% of the RLS patients had diabetes and 70% had hypertension, as did 32% and 63% of controls, respectively.
Stroke occurred in 7.5% of the RLS group and 4.2% of matched controls. The presence of diabetes more than doubled the stroke risk in both groups.
The risk of stroke was 18.2% in diabetic women with RLS and 7% in diabetic men with RLS. In a multivariate analysis that controlled for potential confounding factors, this translated to a threefold increased stroke risk.
Diabetes was associated with a doubling of stroke risk in subjects without RLS, but the risk was similar in men and women, according to Ms. Heis.
In addition to diabetes and female gender, the other major predictor of increased stroke risk in patients with RLS was, not surprisingly, hypertension. It was associated with a 13-fold increased likelihood of stroke, she noted.
RLS was initially linked to increased risk of coronary heart disease in a report from the Nurses’ Health Study (Circulation. 2012 Oct 2;126[14]:1689-94). In 2015, another research group linked more severe RLS to an increased risk of stroke. Ms. Heis and her coinvestigators carried out the current study to test their hypothesis that, since diabetes is a condition that accelerates cardiovascular disease, the endocrine disorder would boost stroke risk more in subjects with RLS than in those without it.
Ms. Heis reported having no financial conflicts regarding her study, which was conducted free of commercial support.
AT ACC 16
Key clinical point: Diabetic women who have restless legs syndrome face a sharply elevated risk of stroke.
Major finding: Stroke occurred in 18.2% of diabetic women with restless legs syndrome, compared with 7% of men.
Data source: This retrospective cohort study included 385 patients with restless legs syndrome and 770 propensity-matched controls.
Disclosures: This study was conducted free of commercial support. The presenter reported having no financial conflicts.
AF and stroke may be temporally related
CHICAGO – One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the prior 30 days, Dr. Rhea C. Pimentel reported at the annual meeting of the American College of Cardiology.
The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) such patients died during their stroke hospitalization, compared with 6 of 83 (7%) whose strokes were not temporally related to atrial fibrillation (AF), noted Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.
Data from the Framingham Heart Study and other sources suggest that stroke in patients who have AF carries about double the mortality rate of strokes in patients without AF. Mortality associated with AF-related stroke in the Kansas study was probably so much higher because the hospital serves as a comprehensive stroke center, drawing patients from considerable distances across the Midwest, she said.
Dr. Pimentel reported on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This is believed to be the largest such patient series ever reported. Their mean age was 73 years, and 41% were women. The mean CHADS2 score was 3.96, with a CHA2DS2-VASc score of 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of AF, and a fifth were on an oral anticoagulant – warfarin, in 70% of cases – at the time of their stroke.
The investigators defined a stroke-related AF episode as a total of at least 1 hour spent in AF during the 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal AF. They typically fulfilled the 1-hour AF requirement via multiple short, self-terminated episodes rather than in an hour-long episode.
Being on an oral anticoagulant had no impact on in-hospital mortality, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel noted that she was presenting the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be very enlightening,” she said.
She and her coinvestigators also plan to subdivide their 30-day study period into 5-day segments to learn just how soon after an AF episode the strokes occurred. Researchers at Stanford (Calif.) University have reported that the greatest stroke risk in patients with AF is in the first 5 days after an AF episode, and the Kansas group would like to confirm that observation.
In addition, because it remains an unresolved question whether any amount of AF is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of 6 minutes of AF rather than 1 hour during the 30 days prior to stroke.
The study was conducted free of commercial support. Dr. Pimentel reported having no relevant financial conflicts.
CHICAGO – One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the prior 30 days, Dr. Rhea C. Pimentel reported at the annual meeting of the American College of Cardiology.
The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) such patients died during their stroke hospitalization, compared with 6 of 83 (7%) whose strokes were not temporally related to atrial fibrillation (AF), noted Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.
Data from the Framingham Heart Study and other sources suggest that stroke in patients who have AF carries about double the mortality rate of strokes in patients without AF. Mortality associated with AF-related stroke in the Kansas study was probably so much higher because the hospital serves as a comprehensive stroke center, drawing patients from considerable distances across the Midwest, she said.
Dr. Pimentel reported on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This is believed to be the largest such patient series ever reported. Their mean age was 73 years, and 41% were women. The mean CHADS2 score was 3.96, with a CHA2DS2-VASc score of 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of AF, and a fifth were on an oral anticoagulant – warfarin, in 70% of cases – at the time of their stroke.
The investigators defined a stroke-related AF episode as a total of at least 1 hour spent in AF during the 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal AF. They typically fulfilled the 1-hour AF requirement via multiple short, self-terminated episodes rather than in an hour-long episode.
Being on an oral anticoagulant had no impact on in-hospital mortality, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel noted that she was presenting the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be very enlightening,” she said.
She and her coinvestigators also plan to subdivide their 30-day study period into 5-day segments to learn just how soon after an AF episode the strokes occurred. Researchers at Stanford (Calif.) University have reported that the greatest stroke risk in patients with AF is in the first 5 days after an AF episode, and the Kansas group would like to confirm that observation.
In addition, because it remains an unresolved question whether any amount of AF is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of 6 minutes of AF rather than 1 hour during the 30 days prior to stroke.
The study was conducted free of commercial support. Dr. Pimentel reported having no relevant financial conflicts.
CHICAGO – One-third of a large cohort of patients with an implantable cardiac device in place at the time of an ischemic stroke had one or more episodes of atrial fibrillation within the prior 30 days, Dr. Rhea C. Pimentel reported at the annual meeting of the American College of Cardiology.
The in-hospital mortality rate of these atrial fibrillation–related strokes was high: 11 of 42 (26%) such patients died during their stroke hospitalization, compared with 6 of 83 (7%) whose strokes were not temporally related to atrial fibrillation (AF), noted Dr. Pimentel, an electrophysiologist at the University of Kansas Medical Center in Kansas City.
Data from the Framingham Heart Study and other sources suggest that stroke in patients who have AF carries about double the mortality rate of strokes in patients without AF. Mortality associated with AF-related stroke in the Kansas study was probably so much higher because the hospital serves as a comprehensive stroke center, drawing patients from considerable distances across the Midwest, she said.
Dr. Pimentel reported on 125 patients who presented with an ischemic stroke when a cardiac monitoring device was in place. This is believed to be the largest such patient series ever reported. Their mean age was 73 years, and 41% were women. The mean CHADS2 score was 3.96, with a CHA2DS2-VASc score of 5.28. Of the patients, 62% had a pacemaker; the rest had an implantable cardioverter-defibrillator or cardiac resynchronization device. One-quarter of the group had a prior history of AF, and a fifth were on an oral anticoagulant – warfarin, in 70% of cases – at the time of their stroke.
The investigators defined a stroke-related AF episode as a total of at least 1 hour spent in AF during the 30 days preceding the stroke. Eighty percent of affected patients had paroxysmal AF. They typically fulfilled the 1-hour AF requirement via multiple short, self-terminated episodes rather than in an hour-long episode.
Being on an oral anticoagulant had no impact on in-hospital mortality, which was 14.2% in patients on warfarin or a newer anticoagulant and 14.3% in those who were not. Dr. Pimentel noted that she was presenting the results of the investigators’ initial look at the data. They are in the process of obtaining the patients’ international normalized ratio data, which “should be very enlightening,” she said.
She and her coinvestigators also plan to subdivide their 30-day study period into 5-day segments to learn just how soon after an AF episode the strokes occurred. Researchers at Stanford (Calif.) University have reported that the greatest stroke risk in patients with AF is in the first 5 days after an AF episode, and the Kansas group would like to confirm that observation.
In addition, because it remains an unresolved question whether any amount of AF is safe, Dr. Pimentel and her coworkers are considering reanalyzing their data using a cutoff of 6 minutes of AF rather than 1 hour during the 30 days prior to stroke.
The study was conducted free of commercial support. Dr. Pimentel reported having no relevant financial conflicts.
AT ACC 16
Key clinical point: One-third of patients with an ischemic stroke while they had an implantable cardiac device had atrial fibrillation in the 30 days prior.
Major finding: The in-hospital mortality rate was 26% in patients with AF-related stroke, compared with 7% in those without AF.
Data source: A single-center, retrospective study of 125 patients who had an ischemic stroke while wearing a pacemaker or other implanted cardiac device.
Disclosures: The study was conducted free of commercial support. The presenter reported having no financial conflicts of interest.
$30 million NIA Consortium Explores Links Between Vascular Health and Alzheimer Disease
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
AT ADRD 2016 SUMMIT
$30 million NIA consortium explores links between vascular health and Alzheimer’s disease
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
On Twitter @Alz_Gal
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
On Twitter @Alz_Gal
BETHESDA, MD. – Cerebral vascular dysfunction exerts a significant negative influence on cognition, doubling the risk of dementia in old age and speeding the rate of cognitive decline.
These findings have been confirmed in a number of studies, and their advancement in both research and clinical arenas continues. But studies of the vascular conditions that affect cognition remain largely observational. Intervention trials are few and limited in scope. The dearth of animal models that express compromised cerebral vascular function has made conducting basic studies feel like wheels spinning in the mud.
According to investigators who discussed the problem at the recent Alzheimer’s Disease–Related Dementias 2016 Summit, sponsored by the National Institutes of Health, the situation calls for a targeted push to better understand vascular complications and their impact on cognition and the development of dementias – and a new, 5-year NIH research program aims to do just that.
M²OVE–AD: Molecular Mechanisms of the Vascular Etiology of Alzheimer’s Disease, is a $30 million initiative that brings together more than a dozen research teams. Investigators will employ new molecular profiling technologies and big data analytics to understand how vascular dysfunction influences the development of Alzheimer’s. The teams will collaborate on five different projects, each exploring a different facet of these complex processes, according to Dr. Suzana Petanceska, program director of the neuroscience division at the National Institute on Aging, Bethesda, Md., who shared her thoughts after the meeting.
“The central goal of the consortium is to generate a deeper understanding of the molecular mechanisms linking vascular risk factors, cerebrovascular disease, and Alzheimer’s, and to generate a new big-data resource that will aid the discovery of therapeutic targets for disease treatment and prevention and molecular signatures that can be used as biomarkers for disease risk,” Dr. Petanceska said in an interview.
Following a new trend of sharing Alzheimer’s research data across public and academic domains, data generated by this program will be made rapidly available to the greater research community. “Making these complex biological data sets available and usable by researchers other than the data generators is key to accelerating the pace at which the research community can generate new knowledge and replicate new findings. The M²OVE–AD initiative builds on the open-science approach established by the Accelerating Medicines Partnership – AD Programand Alzheimer’s Disease Neuroimaging Initiative (ADNI). By coordinating the experimental and analytical approaches the research teams will maximize the usability of the data generated on these projects.”
Five complementary projects comprise the consortium:
Integrative Translational Discovery of Vascular Risk Factors in Aging and Dementia
Researchers at the Mayo Clinics in Minnesota and Florida will collaborate with those at the Icahn Institute for Genomics and Multiscale Biology, New York, to explore how molecular networks influence vascular risk in normal aging, as well as in Alzheimer’s and other dementias.
The project’s goal is to understand how gender and the Alzheimer’s disease risk factor gene ApoE4 influence the molecular processes that lead to Alzheimer’s-related cerebral amyloid angiopathy (CAA).
CAA appears to be a key player in the progression of Alzheimer’s disease. The health of small vessels of the brain is important not only in age-related cognitive decline, but also in amyloid clearance. When amyloid collects in these vessels, it may cause a potentially self-sustaining loop of vascular injury and impaired amyloid clearance, which causes more intravascular amyloid deposition, more CAA, and increasing amyloid pathology.
The team intends to use genetic and expression profiling data from human brain and bloods samples, as well as existing molecular, clinical, and pathologic data in hopes of discovering therapeutic targets. The dynamic interaction between gender, apoE4 and aging and its impact on various AD pathologic and clinical traits will be explored in an array of existing and new animal models.
“Integrating the analysis of multidimensional human data with studies in animal models will accelerate the speed with which the findings can be translated to new interventions for treatment and prevention,” Dr. Petanceska said.
Type 2 diabetes mellitus and prediabetes metabolic abnormalities affect one-third of U.S. adults and the majority of persons aged 60 years and older. Diabetes is associated with a higher risk of the clinical manifestations of AD, including dementia and mild cognitive impairment. Hispanics in the United States have higher rates of diabetes, putting them at greater risk for developing Alzheimer’s. Investigators at Columbia University and SUNY Downstate Medical Center, both in New York, will examine the complex relationship between diabetes, cerebrovascular disease, and Alzheimer’s in a cohort of 200 middle-aged Hispanic participants, with either normal glucose metabolism, prediabetes, or type 2 diabetes; the subjects will be followed for 5 years with whole-brain magnetic resonance imaging and a variety of cognitive measures. The brain imaging will track AD-like functional and pathologic changes and vascular lesions.
In addition, the team will carry out molecular profiling of plasma samples collected in the same participants to identify metabolic and protein signatures that may predict clinical, pathologic, and physiologic outcomes related to Alzheimer’s and cerebrovascular disease.
In a companion study using mouse models with diabetes and Alzheimer’s pathology traits, the researchers will examine how the interaction between diabetes and Alzheimer’s pathology affects the structure and function of neural circuits important to learning and memory.
“This project is addressing two critical knowledge gaps,” Dr. Petanceska said. “The first is understanding the mechanisms by which dysregulated glucose metabolism impacts the onset and progression of pathologic changes in the course of the preclinical phase of Alzheimer’s disease; the second is understanding the molecular determinants of AD risk in Hispanics, a population with higher prevalence of diabetes and at greater risk for AD.”
The Role of Renin-Angiotensin-Endothelial Pathway in Alzheimer’s Disease
Researchers at Emory University, Atlanta, will focus on understanding the molecular mechanisms by which vascular dysfunction associated with high blood pressure affects the onset and progression of Alzheimer’s.
The research cohort comprises 160 subjects from the Emory Cardiovascular Biobank and Predictive Health Study– 80 with normal cognition and 80 with mild cognitive impairment – who will be followed for 2 years. Molecular data (genomic, epigenetic and metabolomic) combined with clinical data on the same subjects collected over 2 years, will be used to build a molecular network model of the interaction between vascular dysfunction and various Alzheimer’s disease traits.
Parallel studies in a rat model that uniquely exhibits human-like AD neuropathology will help uncover the temporal relationship between vascular dysfunction and AD and examine the potential of the molecular regulators of vascular function, such as the renin-angiotensin system, as therapeutic targets for AD. The goal is to characterize this pathway as a therapeutic target.
Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer’s-Type Dementias
Teams at Duke University, Durham, N.C., and the University of Pennsylvania, Philadelphia, will carry out extensive profiling of plasma samples from 900 ADNI participants and from participants in the Duke University MURDOCK Memory and Cognitive Health Study in search for lipid metabolites that are associated with cardiovascular disease and cognitive change. These lipidomic profiles will be integrated with the vast array of clinical and other molecular data available for these participants to identify molecular signatures that may be used to differentiate among various risk-factor types of AD.
In addition, in a subset of subjects, the team will compare the lipidomic profiles between plasma and cerebrospinal fluid; this will enable the team to test hypotheses about the role of systemic vascular and metabolic factors on cognitive aging and AD.
Cerebral Amyloid Angiopathy and Mechanisms of Brain Amyloid Accumulation
Investigators at Massachusetts General Hospital, Boston, will investigate the molecular underpinnings of CAA and its impact on Alzheimer’s disease. Employing a mouse model and human subjects with CAA, the study will explore this cycle of progressive amyloid deposition and brain injury. The team’s approach combines noninvasive detection and analysis of human CAA, real-time measurement of vascular structure and physiology in living transgenic mouse models, and molecular analysis of gene expression in brain microvessels. Ultimately, the team hopes to identify candidate therapies with which could block it.
“This highly multidisciplinary investigation into how the vascular effects of amyloid at the molecular, single-blood vessel, and whole-brain levels influence the clinical disease promises to deliver new, well-characterized therapeutic targets for disease prevention,” Dr. Petanceska said.
She predicted that the wide-ranging projects of the M²OVE–AD consortium will bring invaluable understanding to an enormously important, but still unexplored, aspect of Alzheimer’s pathology.
“We hope that this large-scale team science effort will generate an in-depth understanding of how vascular and metabolic factors contribute to neurodegenerative changes that result in cognitive decline and dementia and that the data and knowledge generated by this program will be the basis for developing effective interventions for disease treatment and prevention.”
On Twitter @Alz_Gal
AT ADRD 2016 SUMMIT
Endovascular thrombectomy procedure volume for stroke may not affect outcomes
VANCOUVER – The relationship between hospitals’ procedural volume and patient outcomes that has been observed for many cardiovascular interventions and other surgeries does not hold for endovascular mechanical thrombectomy procedures for acute ischemic stroke, according to an analysis of cases during 2008-2011 in the Nationwide Inpatient Sample.
In-hospital mortality and rates for any complications were not associated with high or low endovascular mechanical thrombectomy (EMT) volume at hospitals across the United States in the analysis of 13,502 adult patients hospitalized with a primary diagnosis of acute ischemic stroke and treated with EMT, neurology resident Dr. Abhishek Lunagariya of the University of Florida, Gainesville, reported at the annual meeting of the American Academy of Neurology.
A smaller prior study of 2,749 EMTs done in 296 hospitals in 2008 showed lower mortality in high-volume hospitals that performed 10 or more of the procedures per year (J Stroke Cerebrovasc Dis. 2013 Nov; 22[8]:1263-9).
Of the 13,502 EMTs in the study, 25% occurred at low-volume hospitals performing less than 10 per year. Low-volume hospitals had higher in-hospital mortality than did higher-volume centers performing 10 or more of the procedures per year in an unadjusted comparison (26% vs. 21%). A comparison of a combined endpoint for any complications (in-hospital mortality, intracerebral hemorrhage, and vascular complications) was also significantly in favor of high-volume hospitals (34% vs. 30%).
However, in a multivariate hierarchical model, low-volume hospitals were not associated with higher in-hospital mortality (odds ratio, 0.95; 95% confidence interval, 0.74-1.23) or rate of any complications (OR, 0.96; 95% CI, 0.76-1.21). These analyses were adjusted for age, gender, ethnicity, primary payer, median household income, hospital region/teaching status/location/bed size, Charlson Comorbidity Index, calendar year, and use of intravenous tissue plasminogen activator.
Dr. Lunagariya noted that he and his associates could not adjust the comparisons for National Institutes of Health Stroke Scale scores because they are not recorded in the National Inpatient Sample. They also could not examine what happened to patients after discharge.
Dr. Lunagariya suggested a variety of possible reasons that might help to explain the lack of an association between hospital procedure volume and outcomes after adjustment: the availability of better thrombectomy devices since the smaller 2008 study, lesser operator variability, favorable patient selection, and an increased skill set of operators working at low-volume hospitals.
One audience member noted that some endovascular interventionalists will operate at both high-volume and low-volume hospitals and could account for some of the findings. That indeed might be happening more often and needs to happen more often, Dr. Lunagariya said in an interview, in order to combat the “common belief” that it would be better to wait for a patient to undergo the procedure at a high- rather than low-volume hospital. Patients who receive initial care for stroke at a low-volume hospital but are not stable enough or do not have enough time to be transferred could benefit from EMT if an interventionalist who performs EMT drove there instead, he said.
With even newer devices now available that are thought to be easier to use, Dr. Lunagariya suggested that the similarity in outcomes at low- and higher-volume centers may not change in updated analyses of more recent EMT procedures for ischemic stroke.
The investigators received no funding for the study, and they reported having no financial disclosures.
VANCOUVER – The relationship between hospitals’ procedural volume and patient outcomes that has been observed for many cardiovascular interventions and other surgeries does not hold for endovascular mechanical thrombectomy procedures for acute ischemic stroke, according to an analysis of cases during 2008-2011 in the Nationwide Inpatient Sample.
In-hospital mortality and rates for any complications were not associated with high or low endovascular mechanical thrombectomy (EMT) volume at hospitals across the United States in the analysis of 13,502 adult patients hospitalized with a primary diagnosis of acute ischemic stroke and treated with EMT, neurology resident Dr. Abhishek Lunagariya of the University of Florida, Gainesville, reported at the annual meeting of the American Academy of Neurology.
A smaller prior study of 2,749 EMTs done in 296 hospitals in 2008 showed lower mortality in high-volume hospitals that performed 10 or more of the procedures per year (J Stroke Cerebrovasc Dis. 2013 Nov; 22[8]:1263-9).
Of the 13,502 EMTs in the study, 25% occurred at low-volume hospitals performing less than 10 per year. Low-volume hospitals had higher in-hospital mortality than did higher-volume centers performing 10 or more of the procedures per year in an unadjusted comparison (26% vs. 21%). A comparison of a combined endpoint for any complications (in-hospital mortality, intracerebral hemorrhage, and vascular complications) was also significantly in favor of high-volume hospitals (34% vs. 30%).
However, in a multivariate hierarchical model, low-volume hospitals were not associated with higher in-hospital mortality (odds ratio, 0.95; 95% confidence interval, 0.74-1.23) or rate of any complications (OR, 0.96; 95% CI, 0.76-1.21). These analyses were adjusted for age, gender, ethnicity, primary payer, median household income, hospital region/teaching status/location/bed size, Charlson Comorbidity Index, calendar year, and use of intravenous tissue plasminogen activator.
Dr. Lunagariya noted that he and his associates could not adjust the comparisons for National Institutes of Health Stroke Scale scores because they are not recorded in the National Inpatient Sample. They also could not examine what happened to patients after discharge.
Dr. Lunagariya suggested a variety of possible reasons that might help to explain the lack of an association between hospital procedure volume and outcomes after adjustment: the availability of better thrombectomy devices since the smaller 2008 study, lesser operator variability, favorable patient selection, and an increased skill set of operators working at low-volume hospitals.
One audience member noted that some endovascular interventionalists will operate at both high-volume and low-volume hospitals and could account for some of the findings. That indeed might be happening more often and needs to happen more often, Dr. Lunagariya said in an interview, in order to combat the “common belief” that it would be better to wait for a patient to undergo the procedure at a high- rather than low-volume hospital. Patients who receive initial care for stroke at a low-volume hospital but are not stable enough or do not have enough time to be transferred could benefit from EMT if an interventionalist who performs EMT drove there instead, he said.
With even newer devices now available that are thought to be easier to use, Dr. Lunagariya suggested that the similarity in outcomes at low- and higher-volume centers may not change in updated analyses of more recent EMT procedures for ischemic stroke.
The investigators received no funding for the study, and they reported having no financial disclosures.
VANCOUVER – The relationship between hospitals’ procedural volume and patient outcomes that has been observed for many cardiovascular interventions and other surgeries does not hold for endovascular mechanical thrombectomy procedures for acute ischemic stroke, according to an analysis of cases during 2008-2011 in the Nationwide Inpatient Sample.
In-hospital mortality and rates for any complications were not associated with high or low endovascular mechanical thrombectomy (EMT) volume at hospitals across the United States in the analysis of 13,502 adult patients hospitalized with a primary diagnosis of acute ischemic stroke and treated with EMT, neurology resident Dr. Abhishek Lunagariya of the University of Florida, Gainesville, reported at the annual meeting of the American Academy of Neurology.
A smaller prior study of 2,749 EMTs done in 296 hospitals in 2008 showed lower mortality in high-volume hospitals that performed 10 or more of the procedures per year (J Stroke Cerebrovasc Dis. 2013 Nov; 22[8]:1263-9).
Of the 13,502 EMTs in the study, 25% occurred at low-volume hospitals performing less than 10 per year. Low-volume hospitals had higher in-hospital mortality than did higher-volume centers performing 10 or more of the procedures per year in an unadjusted comparison (26% vs. 21%). A comparison of a combined endpoint for any complications (in-hospital mortality, intracerebral hemorrhage, and vascular complications) was also significantly in favor of high-volume hospitals (34% vs. 30%).
However, in a multivariate hierarchical model, low-volume hospitals were not associated with higher in-hospital mortality (odds ratio, 0.95; 95% confidence interval, 0.74-1.23) or rate of any complications (OR, 0.96; 95% CI, 0.76-1.21). These analyses were adjusted for age, gender, ethnicity, primary payer, median household income, hospital region/teaching status/location/bed size, Charlson Comorbidity Index, calendar year, and use of intravenous tissue plasminogen activator.
Dr. Lunagariya noted that he and his associates could not adjust the comparisons for National Institutes of Health Stroke Scale scores because they are not recorded in the National Inpatient Sample. They also could not examine what happened to patients after discharge.
Dr. Lunagariya suggested a variety of possible reasons that might help to explain the lack of an association between hospital procedure volume and outcomes after adjustment: the availability of better thrombectomy devices since the smaller 2008 study, lesser operator variability, favorable patient selection, and an increased skill set of operators working at low-volume hospitals.
One audience member noted that some endovascular interventionalists will operate at both high-volume and low-volume hospitals and could account for some of the findings. That indeed might be happening more often and needs to happen more often, Dr. Lunagariya said in an interview, in order to combat the “common belief” that it would be better to wait for a patient to undergo the procedure at a high- rather than low-volume hospital. Patients who receive initial care for stroke at a low-volume hospital but are not stable enough or do not have enough time to be transferred could benefit from EMT if an interventionalist who performs EMT drove there instead, he said.
With even newer devices now available that are thought to be easier to use, Dr. Lunagariya suggested that the similarity in outcomes at low- and higher-volume centers may not change in updated analyses of more recent EMT procedures for ischemic stroke.
The investigators received no funding for the study, and they reported having no financial disclosures.
AT THE AAN 2016 ANNUAL MEETING
Key clinical point: Patient outcomes after endovascular mechanical thrombectomy for acute ischemic stroke do not appear to be worse at low- versus high-volume hospitals.
Major finding: In a multivariate hierarchical model, low-volume hospitals (fewer than 10 thrombectomies per year) were not associated with higher in-hospital mortality (odds ratio, 0.95; 95% confidence interval, 0.74-1.23) or rate of any complications (OR, 0.96; 95% CI, 0.76-1.21).
Data source: A retrospective review of 13,502 patients with acute ischemic stroke who underwent endovascular mechanical thrombectomy in 2008-2011.
Disclosures: The investigators received no funding for the study, and they reported having no financial disclosures.
VIDEO: New ACC consensus guidance addresses nonstatin therapies
CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.
Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.
“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”
The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.
Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:
•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.
•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.
•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.
•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.
The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).
Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.
In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.
Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.
PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.
The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.
Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.
Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.
Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.
“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”
Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.
sworcester@frontlinemedcom.com
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.
Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.
“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”
The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.
Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:
•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.
•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.
•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.
•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.
The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).
Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.
In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.
Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.
PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.
The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.
Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.
Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.
Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.
“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”
Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.
sworcester@frontlinemedcom.com
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.
Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.
“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”
The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.
Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:
•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.
•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.
•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.
•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.
The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).
Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.
In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.
Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.
PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.
The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.
Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.
Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.
Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.
“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”
Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.
sworcester@frontlinemedcom.com
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ACC 16
Women with suspected CAD classified as lower risk than men
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Despite symptomatic presentation, greater family history of premature coronary artery disease, and higher risk factor burden, including older age and greater prevalence of hypertension and dyslipidemia, the women in PROMISE were more likely to be characterized as low risk based on standard cardiovascular risk assessment scores and thus, not surprisingly, also were considered to be at lower risk by their providers. These findings add credence to the ongoing concerns that women are preferentially likely to receive less intensive management of CAD than their male counterparts.
The 2014 American Heart Association Consensus Statement on noninvasive diagnostic testing in women with suspected ischemic heart disease highlighted the development of novel diagnostic tools that have an expanded role in the evaluation of symptomatic female patients to detect not only focal epicardial coronary stenosis, but also nonobstructive atherosclerosis as well as the identification of ischemia resulting from microvascular dysfunction. Such methods using advanced imaging are making steady progress in the understanding of microvascular disease and its consequences.
We agree with the PROMISE investigators that focused sex-specific diagnostic strategies are needed to reduce the cardiovascular mortality and morbidity in women. With emerging data on the full pathophysiologic spectrum of ischemic heart disease in women, diagnostic algorithms must include functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, for accurately establishing the diagnosis and prognosis of women with suspected IHD.
Dr. Jennifer H. Mieres is with Hofstra University, Hempstead, N.Y. Dr. Robert O. Bonow is with Northwestern University, Chicago. They had no disclosures. These comments are from their editorial (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.0089).
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.
The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.
The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).
Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).
Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.
Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.
“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.
The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
FROM ACC 16
Key clinical point: Women with suspected coronary artery disease had similar symptoms and more risk factors for coronary artery disease, compared with men, but were classified as lower risk on risk scores and by providers.
Major finding: All risk scores assessed women as being at lower risk than men. Providers characterized 41% of pretest women and 34% of men as low risk (P less than .001).
Data source: A prospective, multicenter, randomized trial of 10,003 symptomatic outpatients with suspected coronary artery disease.
Disclosures: The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Dr. Hemal had no disclosures. Senior author Dr. Pamela Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.
