Neurology

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

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

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

The study was simultaneously published online in The Lancet.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Worse disability scores

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

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

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

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

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

No difference in ICH or severe hypotension episodes

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

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

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

What levels should be aimed for?

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

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

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

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

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

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

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

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

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

The study was simultaneously published online in The Lancet.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Worse disability scores

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

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

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

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

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

No difference in ICH or severe hypotension episodes

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

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

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

What levels should be aimed for?

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

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

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

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

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

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

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

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

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

The study was simultaneously published online in The Lancet.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Worse disability scores

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

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

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

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

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

No difference in ICH or severe hypotension episodes

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

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

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

What levels should be aimed for?

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

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

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

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

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

As to whether these results are generalizable to other populations, given that the patients were Chinese, Dr. Anderson noted that Asian people have higher rates of intracranial atherosclerosis and more blood pressure complications in the heart and kidney than White patients. Stroke management patterns also differ.

“These points raise questions about generalizability, and while I think this is an issue for consideration, I do not think it should detract from the clarity of these results,” he commented.

The study is supported by grants from the Shanghai Hospital Development Center, the National Health and Medical Research Council of Australia, the China Stroke Prevention Project, Shanghai Changhai Hospital, the Science and Technology Commission of Shanghai Municipality, Takeda China, Genesis Medtech, and Penumbra. Dr. Anderson has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the UK Medical Research Council, Penumbra, and Takeda China.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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

Patients with acute ischemic stroke presenting late at the hospital can be selected for endovascular thrombectomy by the presence of collateral flow on CT angiography (CTA), a new study shows.

The MR CLEAN-LATE trial found that patients selected for thrombectomy in this way had a greater chance of a better functional outcome than patients who did not receive endovascular therapy.

The study was presented at the 14th World Stroke Congress in Singapore by study investigator Susanne Olthuis, MD, of Maastricht (the Netherlands) University Medical Center.

Patients in the intervention group were more likely to show a benefit on the primary endpoint of modified Rankin Scale (mRS) score at 90 days with a significant common odds ratio of 1.68, a finding that received applause from attendees of the plenary WSC session at which the study was presented.

“This means that patients treated with endovascular therapy in this trial had about a 1.7 times higher chance of achieving a better functional outcome at 90 days,” Dr. Olthuis said.

“Selection based on collateral flow identifies an additional group of patients eligible for late-window endovascular therapy in addition to those eligible based on perfusion and clinical criteria,” Dr. Olthuis concluded.

“We recommend implementation of collateral selection in routine clinical practice as it is time efficient. The CTA is already available, and it involves a low-complexity assessment. The only distinction that needs to be made is whether or not there are any collaterals visible on CTA. If collaterals are absent or there is any doubt, then CT perfusion [CTP] imaging can still be used,” she added.

Co–principal investigator Wim H. van Zwam, MD, interventional radiologist at Maastricht, said in a comment:“My take-home message is that now in the late window we can select patients based on the presence of collaterals on CT angiography, which makes selection easier and faster and more widely available.

“If any collaterals are seen – and that is easily done just by looking at the CTA scan – then the patient can be selected for endovascular treatment,” Dr. van Zwam added. “We don’t need to wait for calculations of core and penumbra volumes from the CTP scan. There will also be additional patients who can benefit from endovascular therapy who do not fulfill the CTP criteria but do have visible collaterals.”

Explaining the background to the study, Dr. Olthuis noted that endovascular thrombectomy for large vessel occlusion stroke is safe and effective if performed within 6 hours and the effect then diminishes over time. In the original trial of endovascular treatment, MR CLEAN, patients with higher collateral grades had more treatment benefit, leading to the hypothesis that the assessment of collateral blood flow could help identify patients who would still benefit in the late time window.

The current MR CLEAN-LATE trial therefore set out to compare safety and efficacy of endovascular therapy in patients with acute ischemic stroke in the anterior circulation presenting within 6-24 hours from symptom onset with patients selected based on the presence of collateral flow on CTA.

At the time the trial was starting, the DAWN and DEFUSE 3 trials reported showing benefit of endovascular therapy in patients presenting in the late window who had been selected for endovascular treatment based on a combination of perfusion imaging and clinical criteria, so patients who fitted these criteria were also excluded from MR CLEAN-LATE as they would now be eligible for endovascular therapy under the latest clinical guidelines. 

But the study continued, as “we believed collateral selection may still be able to identify an additional group of patients that may benefit from endovascular therapy in the late window,” Dr. Olthuis said.

The trial randomly assigned 502 such patients with a National Institutes of Health Stroke Scale (NIHSS) score of at least 2 and with collateral flow grades of 1-3 to receive endovascular therapy (intervention) or control.

Safety data showed a slightly but nonsignificantly higher mortality rate at 90 days in the control group (30%) versus 24% in the intervention group.

The rate of symptomatic intracranial hemorrhage was higher in the intervention group (6.7%) versus 1.6% in the control group, but Dr. Olthuis pointed out that the rate of sICH in the intervention group was similar to that in the endovascular groups of the DAWN and DEFUSE 3 trials.

The primary endpoint – mRS score at 90 days – showed a shift toward better outcome in the intervention group, with an adjusted common OR of 1.68 (95% confidence interval, 1.21-2.33).

The median mRS score in the intervention group was 3 (95% CI, 2-5) versus 4 (95% CI, 2-6) in the control group.

Secondary outcomes also showed benefits for the intervention group for the endpoints of mRS score 0-1 versus 2-6 (OR, 1.63); mRS 0-2 versus 3-6 (OR 1.54); and mRS 0-3 versus 4-6 (OR, 1.74).

In addition, NIHSS score was reduced by 17% at 24 hours and by 27% by 5-7 days or discharge in the intervention group. Recanalization at 24 hours was also improved in the intervention group (81% vs. 52%) and infarct size was reduced by 32%.

Dr. Olthuis explained that collateral grade was defined as the amount of collateral flow in the affected hemisphere as a percentage of the contralateral site, with grade 0 correlating to an absence of collaterals (and these were the only patients excluded).

Grade 1 included patients with 50% or less collaterals, grade 2 more than 50%, and grade 3 excellent collaterals – around 100%. “We included grade 1, 2 and 3, and subgroup analysis suggested no treatment interactions between different collateral grades in the patients included,” she said.

Dr. van Zwam noted that there has been evidence from other studies suggesting that the presence of collateral flow could be used to select patients for late thrombectomy, but MR CLEAN-LATE is the first randomized trial to show this and provides confirmation that this strategy is valid.

“Our results show that patients can be selected with just standard CT angiography imaging and that CT perfusion is not necessary. This will make it easier and faster to select patients especially for centers in low-resource areas who do not yet have CT perfusion imaging,” he commented.

“But even in centers where CT perfusion imaging is performed, these results should mean that we do not have to wait to analyze these results before going ahead with thrombectomy. It will also give us an additional tool, as some patients do not meet the criteria on perfusion imaging but still have identifiable collaterals and thus would now qualify for endovascular thrombectomy,” he added.
 

Could collateral assessment replace CT perfusion?

Commenting on the MR CLEAN-LATE trial, Stefan Kiechl, MD, Medical University of Innsbruck (Austria), who is cochair of the WSC scientific committee, said it was an “excellent study.”

“This study does not rely on advanced imaging (e.g., mismatch) and criteria can easily be interpreted on CT/CTA. If the study is published and all details are available this study may substantially ease endovascular therapy in the late time window,” Dr. Kiechl told this news organization.

Also commenting, Urs Fischer, MD, chairman of the department of neurology at the University Hospital Basel (Switzerland), who was not involved with MR CLEAN-LATE, said: “This is another study that has nicely shown that endovascular therapy in patients in the later time window is highly effective.”

Dr. Fischer said he was not surprised by the results. 

“I was expecting the trial to be positive,” he said. “What we can say is that endovascular therapy in patients with proximal vessel occlusion is a very effective intervention – probably one of the most important interventions in the history of medicine – and now we have another subgroup to whom we can offer this therapy. So, this is an important study that will improve the outcome of many further patients.”

Yvo Roos, MD, professor of acute neurology at University Medical Center, Amsterdam, who was a MR CLEAN-LATE investigator, agreed that the trial has the potential to increase number of patients who can be treated with endovascular therapy.

But both Dr. Roos and Dr. Fischer were not convinced that collateral assessment would replace CT perfusion as the first-line choice in selecting patients for endovascular treatment.

“We need to see what kind of patients were included in the trial and what kind of perfusion imaging characteristics they had, to see how they compare with patients selected by perfusion imaging,” Dr. Roos noted. “I think CT perfusion is here. But if the data shows that collateral score is better able to identify patients for endovascular treatment than CT perfusion, then this has the potential to change practice. But that needs to be shown.”

All patients screened for the MR CLEAN-LATE trial also received CT perfusion imaging as part of the standard imaging protocol, and many were selected for endovascular therapy directly on this basis, so would not have entered the trial. The researchers plan to analyze these results and to compare how the two approaches differ.

MR CLEAN-LATE is an investigator-driven study, funded by the Dutch Heart Foundation, the Brain Foundation Netherlands, and Medtronic. The study was designed and conducted, analyzed, and interpreted by the investigators independently of all sponsors. Dr. Olthuis reported no relevant financial relationships.

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

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Patients with psychotic disorders such as schizophrenia are more than twice as likely as those without a psychotic disorder to eventually develop dementia, new research suggests.

Results from a review and meta-analysis of almost 13 million total participants from nine countries showed that, across multiple different psychotic disorders, there was a 2.5-fold higher risk of developing dementia later in life compared with individuals who did not have a disorder. This was regardless of the age at which the patients first developed the mental illness.

Moreover, participants with a psychotic disorder tended to be younger than average when diagnosed with dementia. Two studies showed that those with psychotic disorders were more likely to be diagnosed with dementia as early as in their 60s.

“The findings add to a growing body of evidence linking psychiatric disorders with later cognitive decline and dementia,” senior investigator Jean Stafford, PhD, a research fellow at MRC Unit for Lifelong Health and Ageing, University College London, told this news organization.

Dr. Stafford noted that the results highlight the importance of being aware of and watchful for symptoms of cognitive decline in patients with psychotic disorders in mid- and late life.

“In addition, given that people with psychotic disorders are at higher risk of experiencing multiple health conditions, including dementia, managing overall physical and mental health in this group is crucial,” she said.

The findings were published online in Psychological Medicine.
 

Bringing the evidence together

There is increasing evidence that multiple psychiatric symptoms and diagnoses are associated with cognitive decline and dementia, with particularly strong evidence for late-life depression, Dr. Stafford said.

“However, the relationship between psychotic disorders and dementia is less well-established,” she added.

Last year, her team published a study showing a strong association between very late onset psychotic disorders, defined as first diagnosed after age 60 years, and increased risk for dementia in Swedish population register data.

“We also became aware of several other large studies on the topic published in the last few years and realized that an up-to-date systematic review and meta-analysis was needed to bring together the evidence, specifically focusing on longitudinal studies,” Dr. Stafford said.

The researchers searched four databases of prospective and retrospective longitudinal studies published through March 2022. Studies were required to focus on adults aged 18 years or older with a clinical diagnosis of a nonaffective psychotic disorder and a comparison group consisting of adults without a nonaffective psychotic disorder.

Of 9,496 papers, the investigators selected 11 published from 2003 to 2022 that met criteria for inclusion in their meta-analysis (12,997,101 participants), with follow-up periods ranging from 1.57 to 33 years.

The studies hailed from Denmark, Finland, Sweden, the United Kingdom, the United States, Australia, Taiwan, New Zealand, and Israel.

Random-effects meta-analyses were used to pool estimates across studies. The researchers assessed the risk of bias for each study. They also included two additional studies in the review, but not the meta-analysis, that focused specifically on late-onset acute and transient psychosis and late-onset delusional disorder.

The other studies focused on late-onset schizophrenia and/or very late onset schizophrenia-like psychoses, schizophrenia, psychotic disorders, and schizophrenia in older people.

Most studies investigated the incidence of all-cause dementia, although one study focused on the incidence of Alzheimer’s disease.
 

Potential mechanisms

The narrative review showed that most studies (n = 10) were of high methodological quality, although two were rated as fair and one as poor.

Almost all studies accounted for basic sociodemographic confounders. Several also adjusted for comorbidities, alcohol/substance use disorders, medications, smoking status, and income/education level.

Pooled estimates from the meta-analyzed studies showed that only one showed no significant association between psychotic disorders and dementia, whereas 10 reported increased risk (pooled risk ratio, 2.52; 95% confidence interval, 1.67-3.80; I², 99.7%).

Subgroup analyses showed higher risk in participants with typical and late-onset psychotic disorders (pooled RR, 2.10; 95% CI, 2.33-4.14; I², 77.5%; P = .004) vs. those with very late onset schizophrenia-like psychoses (pooled RR, 2.77; 95% CI, 1.74-4.40 I², 98.9%; P < .001).

The effect was larger in studies with a follow-up of less than 10 years vs. those with a follow-up of 10 years or more, and it was also greater in studies conducted in non-European vs. European countries (all P < .001).

Studies with more female participants (≥ 60%) showed higher risk compared with those that had a lower percentage of female participants. Studies published during or after 2020 showed a stronger association than those published before 2020 (all P < .001).

There was also a higher risk for dementia in studies investigating broader nonaffective psychotic disorders compared with studies investigating only schizophrenia, in prospective vs. retrospective studies, and in studies with a minimum age of less than 60 years at baseline vs. a minimum age of 60 or older (all P < .001).

“Several possible mechanisms could underlie these findings, although we were not able to directly test these in our review,” Dr. Stafford said. She noted that psychotic disorders and other psychiatric diagnoses may cause dementia.

“People with psychotic disorders such as schizophrenia are also at higher risk of health conditions including cardiovascular disease and diabetes, which are known risk factors for dementia and could underpin these associations,” said Dr. Stafford.

It is also possible “that psychotic symptoms could be early markers of dementia for some people, rather than causes,” she added.
 

Neuroimaging evidence lacking

Commenting on the study, Dilip V. Jeste, MD, former senior associate dean for healthy aging and senior care and distinguished professor of psychiatry and neurosciences at the University of California, San Diego, complimented the investigators for “an excellent article on an important but difficult topic.”

Limitations “pertain not to the meta-analysis but to the original studies,” said Dr. Jeste, who was not involved with the review. Diagnosing dementia in individuals with psychotic disorders is “challenging because cognitive deficits and behavioral symptoms in psychotic disorders may be misdiagnosed as dementia in some individuals – and vice versa,” he added.

Moreover, the studies did not specify the type of dementia, such as Alzheimer’s disease, vascular, Lewy body, frontotemporal, or mixed. Together, “they account for 90% of the dementias, and most patients with these dementias have brain abnormalities that can clearly be seen on MRI,” Dr. Jeste said.

However, patients with schizophrenia who are diagnosed with dementia “rarely show severe brain atrophy, even in specific regions commonly observed in nonpsychotic people with these dementias,” Dr. Jeste noted.

Thus, objective neuroimaging-based evidence for dementia and its subtype “is lacking in most of the published studies of persons with psychotic disorders diagnosed as having dementia,” he said.

There is a “clear need for comprehensive studies of dementia in people with psychotic disorders to understand the significance of the results,” Dr. Jeste concluded.

The review did not receive any funding. Dr. Stafford was supported by an NIHR-UCLH BRC Postdoctoral Bridging Fellowship and the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. Dr. Stafford was also the principal investigator in one of the studies meeting the inclusion criteria of the review. The other investigators and Dr. Jeste reported no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Rates of subarachnoid hemorrhage (SAH) are increasing, particularly in Black people, new research suggests.

Results of a new study based on hospital discharge data show Black people have disproportionately high rates of SAH versus other racial groups. Compared with White and Hispanic people, who had an average of 10 cases per 100,000, or Asian people, with 8 per 100,000 people, Black people had an average of 15 cases per 100,000 population.

Whereas case rates held steady for other racial groups in the study over a 10-year period, Black people were the only racial group for whom SAH incidence increased over time, at a rate of 1.8% per year.

“Root causes of the higher SAH incidence in Black [people] are complex and likely extend beyond simple differences in risk factor characteristics to other socioeconomic factors including level of education, poverty level, lack of insurance, access to quality care, and structural racism,” study investigator Fadar Oliver Otite, MD, assistant professor of neurology at SUNY Upstate Medical University, Syracuse, said in an interview.

“Addressing this racial disparity will require multidisciplinary factors targeted not just at subarachnoid hemorrhage risk factors but also at socioeconomic equity,” he added.

The study was published online in Neurology.
 

Uncontrolled hypertension

The average incidence of SAH for all participants was 11 cases per 100,000 people. Men had an average rate of 10 cases and women an average rate of 13 cases per 100,000.

As expected, incidence increased with age: For middle-aged men, the average was four cases per 100,000 people whereas for men 65 and older, the average was 22 cases.

Dr. Otite and his team combined U.S. Census data with two state hospitalization databases in New York and Florida and found that there were nearly 40,000 people hospitalized for SAH between 2007 and 2017. To find annual incidences of SAH per 100,000 population, they calculated the number of SAH cases and the total adult population for the year.

“Smoking and hypertension are two of the strongest risk factors for subarachnoid hemorrhage,” Dr. Otite said. “Hypertension is more prevalent in Black people in the United States, and Black patients with hypertension are more likely to have it uncontrolled.”
 

Racism, toxic stress

Anjail Sharieff, MD, associate professor of neurology at UT Health, Houston, said aside from a high rate of common SAH risk factors such as hypertension, Black Americans also face a barrage of inequities to health education and quality health care that contributes to higher SAH rates.

“The impact of toxic stress related to racism and discrimination experiences, and chronic stress related to poverty, can contribute to hypertension in Black people,” Dr. Sharieff said, adding that these factors contribute to stroke risk and are not usually accounted for in studies.

Dr. Sharieff said many of her first-time patients end up in her office due to a heart attack or stroke because they were previously uninsured and did not have access to primary care. “We need to begin leveraging trust with people in communities – meeting people where they are,” to educate them about hypertension and other health issues, she said.

A shining example of community engagement to reduce hypertension in Black communities was the Cedars-Sinai Barbershop Study, where 52 barbershops in Los Angeles implemented blood pressure checks and interventions among customers. A year later, the project was still working.

“Once we can identify the health problems in Black communities,” said Dr. Sharieff, “we can treat them.”

Dr. Otite and Dr. Sharieff report no relevant financial relationships.

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

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

Drugs commonly used to treat erectile dysfunction (ED) are not associated with a decreased risk of Alzheimer’s disease and related dementias (ADRD), new research shows.

The findings contradict results from a previous study that suggested that individuals who take sildenafil (Viagra) were significantly less likely to develop Alzheimer’s.

The new research, part of a larger effort to identify existing medications that could be repurposed to treat ADRD, employed a study design that reduced the risk for potential bias that may have influenced the earlier findings, the investigators note.

“That study came out last fall and was widely covered in the media, and we thought there were some methodological shortcomings that might have explained the results,” lead investigator Rishi Desai, PhD, assistant professor of medicine at Harvard Medical School and an associate epidemiologist at Brigham and Women’s Hospital, both in Boston, said in an interview.

The new study was published online in Brain Communications.


 

Not the final word?

Animal studies suggest that phosphodiesterase-5 (PDE5) inhibitors, a drug class that includes the ED drugs sildenafil and tadalafil (Cialis), improve memory and cognitive function and reduce amyloid burden. But studies in humans have yielded conflicting results.*

Although the new research and the work published last year both drew on Medicare data, they examined different patient populations.

The first study compared those who took sildenafil for any reason to those who did not take it. That design likely resulted in an analysis of a comparison of individuals with ED – the most common indication for sildenafil – to generally older individuals with diabetes or hypertension, Dr. Desai said.

In contrast, the current study included only those with pulmonary arterial hypertension (PAH), which is also an indication for PDE5 inhibitors. The researchers compared ADRD incidence in those who took PDE5 inhibitors with the incidence among those who took a different medication to treat their PAH. They used propensity matching to create two groups with similar characteristics and examined the data using four analytic strategies.

The investigators found no significant difference between groups in the incidence of ADRD, regardless of the strategy they used. Cell culture studies also revealed no protective effect from PDE5 inhibitors.

“No study of this kind should claim the final word,” Dr. Desai said. “It is extremely difficult to nail down causality from these types of data sources.”
 

Impressive study design

Commenting on the findings, David Knopman, MD, professor of neurology at Mayo Clinic, Rochester, Minn., described the study design as “impressive” for its efforts to minimize bias, a key limitation in the previous study.

“It was always the case that the claims about sildenafil needed further developmental work prior to testing the drug in randomized controlled trials,” Dr. Knopman said. “The evidence for the use of the drug was never sufficient for clinicians to use it in their patients.”

The study was funded by National Institute on Aging. Dr. Desai is an investigator who receives research grants from Bayer, Vertex, and Novartis that were given to the Brigham and Women’s Hospital for unrelated projects. Dr. Knopman has disclosed no relevant financial relationships.

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

Correction, 11/3/22: An earlier version of this article misstated the abbreviation for phosphodiesterase-5. It is PDE-5.

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

There’s some good overall news in a large analysis that looked at whether a mother’s COVID-19 infection or birth during the pandemic could affect a baby’s brain development.

Researchers studied 21,419 infants who had neurodevelopmental screening during the pandemic (from January 2020 to January 2021) and compared them with babies born before the pandemic (2015-2019).

They found in an analysis of eight studies that, generally, brain development in infants ages 6-12 months old was not changed by COVID-19.
 

Communication skill scores lower than prepandemic

However, one area did see a significant difference when they looked at answers to the Ages and Stages Questionnaire, 3rd edition (ASQ-3): Scores were lower in communication skills.

Compared with the prepandemic babies, the pandemic group of babies was more likely to have communication impairment (odds were 1.7 times higher).

Additionally, mothers’ SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment sector in offspring, with one exception: Odds were 3.5 times higher for fine motor impairment in the pandemic baby group.

The babies in this study were either exposed in the womb to the SARS-CoV-2 infection or screened during the pandemic regardless of whether they were exposed to the virus.

The study, led by Kamran Hessami, MD, with the Maternal Fetal Care Center at Boston Children’s Hospital and Harvard Medical School in Boston, was published in JAMA Network Open.
 

Potential reasons for lower communication skills

The study points to some factors of the pandemic that may be tied to impaired communication skills.

“Higher levels of COVID-19–related stress were reported for both mothers and fathers of infants aged 0-6 months and were associated with insensitive parenting practices, including decreased emotional responsiveness in only mothers, which could lessen the reciprocal exchanges that support language development in early childhood,” they write. “Additionally, opportunities to promote language and social development through new experiences outside the home, including visits with extended family and friends or attendance at a child care center, were lessened for many during the pandemic.”

Viviana M. Fajardo Martinez, MD, with neonatal/perinatal medicine at University of California, Los Angeles, Health, told this publication her team is also studying child development before and after the pandemic over a 3-year period, and delayed communication skills is something she is seeing in clinic there.

She says some parents have been concerned, saying their babies aren’t talking enough or are behind in vocabulary.
 

Babies can catch up after 12 months

One thing she tells parents is that babies who are a bit delayed at 12 months can catch up.

Up to 18 months, they can catch up, she said, adding that they can be reevaluated then for improvement. If, at that point, the baby is not catching up, “that’s when we refer for early intervention,” she said.

Dr. Martinez also tells parents concerned about their infant’s communication skills that it’s important to talk, read, and sing to their child. She said amid pandemic stress, corners may have been cut in asking children to use language skills.

For instance, if a child points to an apple, a stressed parent may just give the child the apple instead of asking the child to request it by name and repeat the word several times.

She also said a limitation of this study is the use of the ASQ-3 questionnaire, which is filled out by parents. Answers are subjective, she notes, and sometimes differ between one child’s two parents. The questionnaire was commonly used during the pandemic because a more objective, professional evaluation has been more difficult.

However, a measure like the Bayley Scales of Infant and Toddler Development Screening Test adds objectivity and will likely give a better picture as research progresses, Dr. Martinez said. 
 

Some information missing

Andréane Lavallée, PhD, and Dani Dumitriu, MD, PhD, both with the department of pediatrics at Columbia University, New York, write in an invited commentary that the overall positive message of the study “should not make researchers complacent” and results should be viewed with caution.

They point out that the precise effects of this novel virus are still unclear and the age group and variables studied may not tell the whole story.

“It should be noted that this systematic review did not consider timing of exposure during pregnancy, maternal infection severity, or exposure to various SARS-CoV-2 variants – all factors that could eventually be proven to contribute to subtle adverse neurodevelopmental outcomes,” they write.

Additionally, past pandemics “such as the 1918 Spanish flu, 1964 rubella, and 2009 H1N1” have taught researchers to watch for increases in diagnoses such as autism spectrum disorder (ASD) and schizophrenia in subsequent years.

“ASD is generally diagnosed at age 3-5 years (and often not until early teens), while schizophrenia is generally diagnosed in mid-to-late 20s,” the editorialists point out. The authors agree and emphasize the need for long-term studies.

Authors report no relevant financial relationships. Editorialist Dr. Dumitriu reports grants from National Institute of Mental Health, the U.S. Centers for Disease Control and Prevention, and the W. K. Kellogg Foundation; and has received gift funds from Einhorn Collaborative during the conduct of the study to the Nurture Science Program, for which Dr Dumitriu serves as director. Dr. Dumitriu received personal fees from Medela outside the submitted work; and is the corresponding author for one of the studies (Shuffrey et al., 2022) included in the systematic review conducted by Dr. Hessami et al. Dr. Lavallée reports grants from the Canadian Institutes of Health Research. Dr. Martinez reports no relevant financial relationships.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

CINCINNATI – Sickle cell disease is well known for its associated anemia, but patients experience a range of other complications as well. These include vision and kidney problems, delayed growth, susceptibility to infection, and pain.

Another issue, not always as well recognized, is a considerably heightened risk for childhood stroke. “Children with sickle cell disease have 100 times the risk of stroke as other children without sickle cell disease, and there’s also an elevated risk of five times the general population in adults with sickle cell disease,” said Lori Jordan, MD, PhD, in an interview.

At the 2022 annual meeting of the Child Neurology Society, Dr. Jordan spoke about stroke as a complication of sickle cell disease, and the role that neurologists can play in preventing primary or secondary strokes. “At least in children, studies have shown that if we screen and identify patients who are at highest risk of stroke, there are primary prevention therapies – usually implemented by hematologists, but that neurologists often are involved with – both monitoring for cognitive effects of silent cerebral infarct and also with treating patients who unfortunately still have an acute stroke,” said Dr. Jordan, who is an associate professor of pediatrics, neurology, and radiology at Vanderbilt University Medical Center, Nashville, Tenn. She also is director of the pediatric stroke program at Vanderbilt.
 

Time is of the essence

“In general, stroke in children is rare, but it’s more common in sickle cell disease, so it’s really important for providers to know that stroke risk is higher in those patients, particularly in those children, and then identify it and treat it earlier. Time is of the essence, and if we can give them the same therapeutics that we give the general stroke population, then time really becomes a factor, so it’s important that people know that it’s an issue for this population,” said Eboni Lance, MD, PhD, who coordinated the session where Dr. Jordan spoke.

Sickle cell disease is caused by a double mutation in the gene encoding the hemoglobin gene, producing the altered sickle hemoglobin (hemoglobin S). The change causes the hemoglobin proteins to tend to stick to one another, which can lead red blood cells to adopt a sickle-like shape. The sickle-shaped blood cells in turn have a tendency to aggregate and can block blood flow or lead to endothelial injury. Symptoms of stroke in children can include hemiparesis, aphasia, and seizure, but they can also be silent.

If no preventive is employed, one in nine with sickle cell disease will experience a stroke by the age of 19. Cerebrovascular symptoms are the most frequent debilitating complication of the condition. Nearly 40% of patients with sickle cell disease will have a silent cerebral infarct by age 18, as will 50% by age 30. Silent strokes have been associated with worse educational attainment and a greater need for educational special services.

Factors contributing to stroke in children with sickle cell disease include anemia and a low blood oxygen count, reduced oxygen affinity of hemoglobin variant, and cerebral vasculopathy. An estimated 10%-15% of young adults with sickle cell disease have severe intracranial stenosis.
 

Primary and secondary stroke prevention strategies

The dire consequences of stroke in this patient population underline the importance of primary stroke prevention, which requires the use of transcranial Doppler (TCD) ultrasound. It has been validated as a tool to screen for initial stroke risk in children with no history of stroke. High velocity measured on TCD indicates a narrowed blood vessel or elevated blood that is compensating for anemia. It adds up to a “struggling brain,” said Dr. Jordan, during her talk. If the TCD ultrasound velocity is greater than 200 cm/sec (or 170 cm/sec, depending on nonimaging versus imaging TCD), the TWiTCH trial showed that seven monthly transfusions is the number needed to treat to prevent one stroke. After 1 year, patients can be switched from transfusions to hydroxyurea if the patient has no significant intracranial stenosis. Hydroxyurea boosts both fetal and total hemoglobin, and also counters inflammation.

Following an acute stroke or transient ischemic attack, patients should receive a transfusion within 2 hours of presenting in the health care setting. American Society of Hematology guidelines recommend exchange transfusion rather than a simple transfusion. A simple transfusion can be initiated if an exchange transfusion is not available within 2 hours and hemoglobin values are less than 8.5 g/dL, to be followed by performance of exchange transfusion when available.

For chronic secondary stroke prevention, transfusions should be performed approximately monthly with the goal of maintaining hemoglobin above 9 g/dL at all times, as well as suppressing hemoglobin S levels to 30% or less of total hemoglobin.

Sudden, severe headache is a potential harbinger of complications like aneurysm, which occurs 10-fold more often among patients with sickle cell disease than the general population. It could also indicate increased intracranial pressure or cerebral venous sinus thrombosis.

Treatment of acute headache in sickle cell disease should avoid use of triptans, since vasoconstriction can counter the increased cerebral blood flow that compensates for anemia. Gabapentin and amitriptyline are good treatment choices.

New-onset seizures are a potential sign of stroke or posterior reversible leukoencephalopathy (PRES) in patients with sickle cell disease. Urgent MRI should be considered for all new-onset seizures. If blood pressure is high, PRES may be present. Seizures may also be an indicator of a previous brain injury.

Dr. Jordan has no relevant financial disclosures. Dr. Lance has served on an advisory board for Novartis.
 

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

Administering D-cycloserine (DCS) along with transmagnetic stimulation (TMS) may be a promising strategy to improve outcomes in major depressive disorder (MDD), new research suggests.

“The take-home message is that this proof-of-concept study opens up a new avenue of treatment research so that in the future, we may be able to provide our patients with safe and well-tolerated medications and enhance noninvasive brain stimulation treatments for depression,” senior author Alexander McGirr, MD, PhD, assistant professor of psychiatry, University of Calgary (Alta.), told this news organization.

“Once the safety and efficacy of this strategy have been confirmed with larger multisite studies, this could be deployed within existing health care infrastructure,” he said.

The study was published online in JAMA Psychiatry.

Synaptic plasticity

Repetitive transmagnetic stimulation (rTMS) and the more recently developed intermittent theta-burst stimulation (iTBS) are noninvasive brain stimulation modalities that have the largest evidence base in improving MDD. Although efficacious, an “unacceptable proportion of patients do not significantly improve” with these approaches, the authors write.

“We believe that iTBS improves depression through a process called synaptic plasticity, or how neurons adapt to stimulation, but we know that synaptic plasticity is impacted by the illness,” Dr. McGirr explained. This “could be the reason that only some patients benefit.”

One potential strategy to enhance neuroplasticity is to administer an adjunctive N-methyl D-aspartate (NMDA) receptor agonist during stimulation, since the NMDA receptor is a “key regulator of synaptic plasticity,” the authors state. In fact, synaptic plasticity with continuous and intermittent TBS is NMDA-receptor–dependent.

“DCS is an NMDA receptor partial agonist, and so at the low dose we used in our trial (100 mg), it can facilitate NMDA receptor signaling. The hypothesis was that pairing it with iTBS would enhance synaptic plasticity and clinical outcomes,” Dr. McGirr said.

The group’s previous research demonstrated that targeting the NMDA receptor with low-dose DCS “normalizes long-term motor cortex plasticity in individuals with MDD.” It also led to greater persistence of iTBS-induced changes compared to placebo.

However, “a demonstration that these physiological effects have an impact on treatment outcomes is lacking,” the authors note.

To address this gap, the researchers conducted a 4-week double-blind, placebo-controlled trial in which 50 participants (mean [standard deviation] age, 40.8 [13.4] years; 62% women) were randomly assigned on a 1:1 basis to receive either iTBS plus DCS or iTBS plus placebo (n = 25 per group) for the first 2 weeks of the trial, followed by iTBS without an adjunct for the third and fourth weeks.

Participants were required to be experiencing a major depressive episode and to have failed to respond to at least one adequate antidepressant trial or psychotherapy (but not more than four adequate antidepressant trials during the current episode).

Patients with acute suicidality, psychosis, recent substance use disorder, benzodiazepine use, seizures, unstable medical conditions, history of nonresponse to rTMS or electroconvulsive therapy, or comorbid psychiatric conditions, as well as those for whom psychotherapy was initiated within 3 months of enrollment or during the trial, were excluded.

Depression was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (changes in score constituted the primary outcome) and the 17-item Hamilton Depression Rating Scale (17-HDRS).

“Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores,” the authors state.
 

“Promising” findings

Most participants in the iTBS plus placebo group were White (80%); 12% were Asian, and 8% were classified as “other.” A smaller proportion of participants in the iTBS plus DCS group were White (68%); the next smallest group was Asian (16%), followed by Hispanic (12%), and “other” (4%).

Participants presented with moderate-severe depressive symptoms, as measured by both the HRDS-17 and the MADRS. The placebo and intervention groups had similar scores at baseline. Resting motor threshold did not differ significantly between the groups, either at baseline or between the weeks with and without adjunctive treatment.

Greater improvements in MADRS scores were found in the intervention group than in the placebo groups (mean difference, –6.15 [95% confidence interval, –2.43 to –9.88]; Hedges g, 0.99 [0.34-1.62]).

A larger treatment effect was found after 4 weeks of treatment than after 2 weeks, although the adjuvant was present for the first 2 weeks. “We speculate that, despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score, compared with 9 of 25 participants (36%) in the iTBS plus DCS group,” the authors write.

The intervention group showed higher rates of clinical response compared to the placebo group (73.9% vs. 29.3%, respectively), as well as higher rates of clinical remission (39.1% vs. 4.2%, respectively), as reflected in lower CGI-severity ratings and greater CGI-improvement ratings.

There were no serious adverse events during the trial.

The authors note several limitations, including the small sample size and the fact that participants received the adjunctive treatment for only 2 weeks. Longer treatment courses “require dedicated study.” And the short length of the trial (only 4 weeks) meant the difference between “treatment acceleration” and “treatment enhancement” could not be determined.

Nevertheless, the results are “promising” and suggest additional investigation into “intersectional approaches with other dosing regimens and precision medicine targeting approaches,” the authors state.
 

Synergistic approach

Commenting on the study, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Md., called the findings “heartening.” He noted that the study “demonstrates a creative approach of combining an FDA-approved antibiotic with NMDA partial agonist activity – D-cycloserine – with a brief course of iTBS with the aim of enhancing the neuronal plasticity iTBS creates.”

Dr. Aaronson, who is also an adjunct professor at the University of Maryland, Baltimore, and was not involved with the study, added, “This is an early demonstration of the ability to further exploit neuronal changes from neurostimulation by synergistic use of a pharmacologic intervention.”

The study was supported in part by a Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation. Dr. McGirr has a patent for PCT/CA2022/050839 pending with MCGRx Corp and is a shareholder of MCGRx Corp. The other authors’ disclosures are listed on the original article. Dr. Aaronson is a consultant for Neuronetics.

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

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

A 67-year-old man asks about what he can do to prevent dementia. He reports his mother had dementia, and he wants to do everything he can to prevent it. Which of the following has evidence of benefit?

A) Thiamine

B) Vitamin E

C) Multivitamin (MV)

D) Keto diet

E) Red wine
 

FDA-approved therapies for dementia

To date the actual therapies for dementia have been disappointing. Donepezil, the most prescribed medication for the treatment of dementia has a number-needed-to treat (NNT) over 17, and causes frequent side effects. Aducanumab was recently approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD), but controversy has arisen, as the clinical results were modest, and the price tag will be large – estimated at $30,000-$50,000/year.

Preventive options that may decrease the likelihood of dementia

Patients often ask the question stated above. Regarding how to respond to that question, choice C, MV, has some recent evidence of benefit. Baker and colleagues studied the effect of cocoa extract and multivitamins on cognitive function in the COSMOS-Mind trial.¹ A total of 2,262 people were enrolled, and over 90% completed baseline and at least one annual cognitive assessment. Cocoa extract had no impact on global cognition (confidence interval [CI], –.02-.08, P = .28), but MV supplementation did have a statistically significant impact on global cognition (CI, .02-.12, P less than .007).

Vitamin E has been enthusiastically endorsed in the past as a treatment to prevent cognitive decline. The most recent Cochrane review on vitamin E concluded there was no evidence that the alpha-tocopherol form of vitamin E given to people with MCI prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.²

Exercise has long been a mainstay of our advice to patients as something they can do to help prevent dementia. Yu and colleagues did a meta-analysis of almost 400 randomized controlled trials and observational studies to grade the evidence on different interventions.³ They gave exercise a grade B for evidence of benefit.

A recent study addressed this issue, and I think it is helpful on quantifying how much exercise is needed. Del Pozo Cruz and colleagues did a prospective population-based cohort study of 78,000 adults aged 40-79, with an average of 6.9 years of follow up.⁴ The optimal step count was 9,826 steps (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62) and the minimal step count for benefit was 3,826 steps (HR, 0.75; 95% CI, 0.67-0.83).
 

Modifiable factors

The other major modifiable factors to consider are problems with special senses. Both vision loss and hearing loss have been associated with cognitive impairment.

Shang and colleagues published a meta-analysis of 14 cohort studies addressing vision impairment and cognitive function involving more than 6 million individuals.⁵ They concluded that vision impairment is associated with an increased risk of both dementia and cognitive impairment in older adults.

Loughrey and colleagues performed a meta-analysis of 36 studies addressing hearing loss and cognitive decline.⁶ They reported that, among cross-sectional studies, a significant association was found for cognitive impairment (odds ratio [OR], 2.00; 95% CI, 1.39-2.89) and dementia (OR, 2.42; 95% CI, 1.24-4.72). A similar finding was present in prospective cohort studies with a significant association being found for cognitive impairment (OR, 1.22; 95% CI, 1.09-1.36) and dementia (OR, 1.28; 95% CI, 1.02-1.59).

A 25-year prospective, population-based study of patients with hearing loss revealed a difference in the rate of change in MMSE score over the 25-year follow-up between participants with hearing loss not using hearing aids matched with controls who didn’t have hearing loss. Those with untreated hearing loss had more cognitive decline than that of patients without hearing loss.⁷ The subjects with hearing loss using a hearing aid had no difference in cognitive decline from controls.
 

Pearl

Several simple and safe interventions may protect our patients from cognitive decline. These include taking a daily multivitamin, walking more than 4,000 steps a day, and optimizing vision and hearing.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Baker LD et al. Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer’s Dement. 2022 Sep 14. doi: 10.1002/alz.12767.

2. Farina N et al. Vitamin E for Alzheimer’s dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017 Apr 18;4(4):CD002854. doi: 10.1002/14651858.CD002854.pub5.

3. Yu JT et al. Evidence-based prevention of Alzheimer’s disease: Systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020 Nov;91(11):1201-9.

4. Del Pozo Cruz B et al. Association of daily step count and intensity with incident dementia in 78,430 adults living in the UK. JAMA Neurol. 2022 Oct 1;79(10):1059-63.

5. Shang X et al. The association between vision impairment and incidence of dementia and cognitive impairment: A systematic review and meta-analysis. Ophthalmology. 2021 Aug;128(8):1135-49.

6. Loughrey DG et al. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg. 2018 Feb 1;144(2):115-26.

7. Amieva H et al. Self-reported hearing loss, hearing aids, and cognitive decline in elderly adults: A 25-year study. J Am Geriatr Soc. 2015 Oct;63(10):2099-104.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.

Cocaine, methamphetamine, opioids, and cannabis may independently increase risk of atrial fibrillation (AFib), based on data from almost 24 million people.

While more work is needed to uncover causal links, physicians should be aware that these commonly abused substances could be driving new cases of AFib, reported investigators from the University of California, San Francisco.

“Though alcohol and tobacco smoking have each been associated with a heightened risk of [AFib], relationships between other drug use and [AFib] are poorly understood,” they wrote in European Heart Journal.

Some previous studies have ventured into this terrain, but most focused on fatal arrhythmias, or offered anecdotal evidence. This knowledge gap is particularly concerning for cannabis, the researchers noted, as medical and recreational use are on the rise.

American Heart Association

The present analysis included data from 23.5 million adults in California who received care through a hospital, emergency department, or outpatient surgery center during 2005-2015. Based on ICD-9 diagnostic codes, 132,834 of these patients used cannabis, 98,271 used methamphetamines, 48,701 used cocaine, and 10,032 used opiates. Inclusion required lack of AFib at baseline.

Reliance on ICD-9 codes makes the data “quite specific,” but lacking sensitivity, according to principal author Gregory M. Marcus, MD, cardiologist and professor of medicine at UCSF.

“If they were designated as using these drugs, that is very likely true,” Dr. Marcus said in an interview. “But certainly, the absence of any mention of use of these drugs does not exclude the possibility that some people were still using them. That would not create spurious false-positive relationships; if anything, it attenuates existing relationships.”

In other words, using ICD-9 codes reduced the power to detect an association between each drug and AFib, meaning any relationship needed to be sufficiently strong enough to generate a significant result.

At the end of the decade-long study period, 998,747 patients (4.2%) had developed incident AFib. After adjusting for potential confounders and mediators, all four drugs showed significant, independent associations with AFib. Methamphetamines presented the greatest risk (hazard ratio, 1.86%), followed by opiates (HR, 1.74), cocaine (HR, 1.61), and cannabis (HR, 1.35).

“Our findings provide the first evidence utilizing a longitudinal cohort to demonstrate that cannabis use predicts the future onset of AFib,” Dr. Marcus and colleagues wrote.

Dose-response relationships were not detected for any of the substances; however, usage levels were also derived from ICD-9 codes, which may have been insufficient for this purpose, according to the investigators.
 

Causal mechanisms deserve a closer look

Causal links between AFib and each of the drugs remain unclear. Citing prior research, Dr. Marcus and colleagues explained how methamphetamines are capable of “significant cardiac electrical remodeling,” while cocaine may cause sodium channel dysregulation, and opioids can render atrial myocytes more susceptible to oxidative damage. Although cannabis has previously been linked with hospitalization for arrhythmia, a pharmacologic driver of this phenomenon remains largely unexamined.

“We don’t know for sure precisely what the constituents are that are responsible for our findings,” Dr. Marcus said. “It’s possible that there are some effects that are much more generic, such as inhaling a burned substance. There is good evidence that if you inhale pretty much any sort of particulate matter, that increases inflammation in the body. Inflammation is known to be a trigger for atrial fibrillation.”

Alternatively, all four drugs – whether stimulants or depressants – cause “quite dramatic and often rapid effects on the autonomic nervous system,” Dr. Marcus said, noting that these rapid swings are a known trigger for AFib.

Brian Olshansky, MD, emeritus professor of internal medicine-cardiovascular medicine at the University of Iowa, Iowa City, suggested that nonpharmacologic factors are likely also playing a role.

“All these drugs have slightly different mechanisms of action, so there’s not one mechanism that would explain why all of them would cause atrial fibrillation,” Dr. Olshansky said in an interview. “That does suggest that there’s something else going on, besides just the drug itself. It would be potentially concerning if we were to lay the blame totally on these drugs.”

Dr. Olshansky, who recently coauthored a review of stimulant drugs and arrhythmias, suggested that lifestyle, comorbidities, and drug impurities may have added to the risk of AF.

“[The investigators] did try to correct for that kind of stuff, but it’s very hard to correct for a lot of the issues that may be ongoing with individuals who partake in these drugs,” Dr. Olshansky said in an interview. “They may not be a healthy lot, in general.”

Still, considering previous data linking drugs of abuse with arrhythmias, he said the detected risks were “intriguing,” and deserved a closer look.

“It’s a nice groundbreaking study, with regard to the fact that they showed unique relationships that we don’t completely understand,” Dr. Olshansky said. “It opens up a new opportunity for further investigation.”

The investigators disclosed relationships with InCarda, Baylis Medical, Johnson & Johnson, and others. Dr. Olshansky disclosed no relevant competing interests.