Cardiology News

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

After patients with peripheral artery disease undergo lower-extremity revascularization, they are at high risk for major adverse limb events, and new findings from a prespecified analysis of data from the VOYAGER-PAD trial show that treatment with the direct-acting oral anticoagulant rivaroxaban along with aspirin significantly cut the rate of total major adverse limb events in these patients.

courtesy American College of Cardiology

These findings confirm the drop in first major adverse limb events linked to rivaroxaban treatment that was VOYAGER-PAD’s primary result, reported just over a year ago.

The new total-event analysis also provides important insight into the huge magnitude of total major adverse limb events that patients with PAD can develop following lower-extremity revascularization (LER).

The 6,564 patients who all received aspirin and were randomized to either rivaroxaban (Xarelto) or placebo had 4,714 total events during a median follow-up of 2.5 years following their revascularization procedure. This included 1,092 first primary events (a composite of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death), 522 primary events that occurred as second or subsequent events among patients after a first primary event (a nearly 50% increase from first events only), and 3,100 additional vascular events that did not fit into the primary-event category, most often a peripheral revascularization procedure, Rupert M. Bauersachs, MD, said at the annual scientific sessions of the American College of Cardiology.

“We were all astonished by this high event rate,” Dr. Bauersachs said during his report.

The total-event analysis that he reported showed that treatment with rivaroxaban resulted in a significant 14% relative reduction, compared with placebo in the incidence of total primary events, which closely tracks the significant 15% relative reduction in first primary events reported from the VOYAGER-PAD trial in 2020. Treatment with rivaroxaban also significantly linked with a 14% cut in total vascular events, compared with placebo, including the many events not included in the primary endpoint, said Dr. Bauersachs, who until his retirement in May 2021 was director of the Clinic for Vascular Medicine at the Darmstadt (Germany) Clinic. Concurrently with the report, the results appeared online.

“If one focuses only on first events, you miss the totality of disease burden. There is even greater benefit by reducing total events,” Dr. Bauersachs said during a press briefing. Adding rivaroxaban prevented roughly 2.6 first primary events for every 100 patients treated, but it also prevented 4.4 total primary events and 12.5 total vascular events for every 100 treated patients.

An ‘incredibly high’ event rate

“I don’t think any of us imagined the level of morbidity in this population. The event rate is incredibly high,” commented Joshua A. Beckman, MD, professor and director of vascular medicine at Vanderbilt University Medical Center, Nashville, Tenn.

Because treatment with rivaroxaban showed clear efficacy for also preventing subsequent events it should not be considered to have failed in patients who have a vascular event while on rivaroxaban treatment, he added as designated discussant for the report. Treatment with rivaroxaban “should be continued indefinitely,” he concluded.

“It’s quite astonishing to see the magnitude of [total] events in these patients,” commented Sahil A. Parikh, MD, a cardiologist and director of endovascular services at Columbia University Medical Center in New York. “We’ve always known that these are high-risk patients, but exactly how high their risk is was not well understood until these data came to light.”

Dr. Parikh also noted that, despite the clear evidence reported from VOYAGER-PAD more than a year ago proving the efficacy and safety of adding rivaroxaban to aspirin for long-term treatment of patients with PAD following LER, this regimen has not yet become standard U.S. practice.
 

Rivaroxaban use falls short of the expected level

“This paradigm shift has not seen the level of adoption that we would expect based on the data,” he said. “There have been numerous editorials and discussions of this at every major medical meeting” during the past year, but those expert opinions have not translated into changed practice. “Perhaps the pandemic has muted enthusiasm for adoption of a new therapeutic paradigm,” suggested Dr. Parikh, and “on top of that guidelines have yet to be updated,” although he noted that updated guidelines from the ACC and American Heart Association for PAD that include the types of patients enrolled in VOYAGER-PAD are now under review and should be released by the first half of 2022.

“I think the additional data [reported by Dr. Bauersachs] will encourage us to use rivaroxaban in patients with claudication,” Dr. Parikh said. “Perhaps we should use rivaroxaban and aspirin in a broader swath of patients, but it will take time to convince some constituencies.”

VOYAGER-PAD randomized patients with PAD who underwent successful LER within 10 days prior to enrollment at 542 sites in 34 countries during 2015-2018. In addition to every patient receiving 100 mg aspirin daily and either 2.5 mg rivaroxaban twice daily or placebo once daily, patients who received an intra-arterial device such as a stent could also receive the antiplatelet agent clopidogrel for a planned maximum of 30 days after revascularization at the discretion of their physician, and the trial protocol allowed for extending clopidogrel treatment to as many as 60 days.

In addition to the efficacy outcomes, the safety results showed that adding rivaroxaban to aspirin appeared to increase bleeding episodes, but at rates that generally did not reach significance and that were dwarfed by the efficacy benefit. The study’s primary safety outcome was the incidence of Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, which occurred in 2.65% of patients who received rivaroxaban and in 1.87% on those on placebo, a 43% relative increase that fell short of significance (P = .07). The analyses overall indicated that 10,000 similar patients treated for 1 year with rivaroxaban would have 181 fewer primary events, compared with placebo-treated patients at the cost of also having 29 additional TIMI major bleeding events compared with patient on placebo.

Adding clopidogrel adds little except bleeding

Further analysis showed that just over half of enrolled patients also received clopidogrel for a median of 29 days following their LER procedure. This added agent produced no significant added benefit during 3-year follow-up, but did boost bleeding risk, especially in patients who received clopidogrel for more than 30 days. This led the study investigators to suggest that, while rivaroxaban plus aspirin is indicated for long-term treatment, addition of clopidogrel on top of this should be limited to 30 days or fewer to minimize bleeding risk.

“I’m sure there is a bleeding hazard associated with rivaroxaban plus aspirin, but this is attenuated by using dual therapy and not using triple therapy” by also adding clopidogrel, noted Dr. Parikh.

The new VOYAGER-PAD results also showed that the ongoing risk faced by patients with PAD following LER applies globally to their peripheral arteries. Of the 3,034 total peripheral revascularizations performed in the cohort during follow-up, 64% occurred in the index limb and 36% in the contralateral limb. Another striking finding was that the need for ipsilateral repeat revascularization was more common after an index endovascular procedure, 2,329 repeat revascularizations in 4,379 of these patients (53%), compared with 2,185 patients who had surgical revascularization for their index procedure and subsequently 705 of these patients (32%) needed repeat revascularization.

But rivaroxaban treatment appeared to provide little benefit for the much less frequent incidence of first and subsequent events in the coronary and cerebral circulation. During follow-up, the rates of major adverse cardiovascular events – cardiovascular death, nonfatal MI, and nonfatal stroke – were virtually identical in the rivaroxaban and placebo groups.

“This study makes it clear that we are learning about differences in presentation between the vascular beds, and the benefits of specific treatments in each vascular bed,” Dr. Beckman said.

VOYAGER-PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). Dr. Bauersachs has received personal fees from Bayer, as well as from Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer, and has received grant support from Aspen Pharma. Dr. Beckman been a consultant to and received honoraria from Janssen, as well as from Amgen, JanOne, Novartis, and Sanofi, and he has served on a data and safety monitoring board for Bayer. Dr. Parikh has been a consultant to and received honoraria from Janssen, as well as from Abbott, Boston Scientific, Cordis, Medtronic, Penumbra, Philips, and Terumo, he has been a speaker on behalf of Inari, and he has received grant support from Abbott, Shockwave Medical, Surmodics, and TriReme Medical.

mzoler@mdedge.com

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

The first cases of large vessel arterial occlusion strokes linked to the AstraZeneca COVID-19 vaccine have been described in the United Kingdom. The three cases (one of which was fatal) occurred in two women and one man in their 30s or 40s and involved blockages of the carotid and middle cerebral artery. Two of the three patients also had venous thrombosis involving the portal and cerebral venous system. All three also had extremely low platelet counts, confirmed antibodies to platelet factor 4, and raised D-dimer levels, all characteristic of the vaccine-induced immune thrombotic thrombocytopenia (VITT) reaction associated with the AstraZeneca vaccine.  

They are described in detail in a letter published online on May 25 in the Journal of Neurology, Neurosurgery & Psychiatry

“These are [the] first detailed reports of arterial stroke believed to be caused by VITT after the AstraZeneca COVID vaccine, although stroke has been mentioned previously in the VITT data,” said senior author David Werring, PhD, FRCP.

“VITT has more commonly presented as CVST [Cerebral venous sinus thrombosis] which is stroke caused by a venous thrombosis; these cases are showing that it can also cause stroke caused by an arterial thrombosis,” explained Dr. Werring, professor of clinical neurology at the Stroke Research Centre, University College London.

“In patients who present with ischemic stroke, especially younger patients, and who have had the AstraZeneca vaccine within the past month, clinicians need to consider VITT as a possible cause, as there is a specific treatment needed for this syndrome,” he said.  

Young patients presenting with ischemic stroke after receiving the AstraZeneca vaccine should urgently be evaluated for VITT with laboratory tests, including platelet count, D-dimers, fibrinogen, and anti-PF4 antibodies, the authors wrote, and then managed by a multidisciplinary team, including hematology, neurology, stroke, neurosurgery, and neuroradiology, for rapid access to treatments including intravenous immune globulin, methylprednisolone, plasmapheresis, and nonheparin anticoagulants such as fondaparinux, argatroban, or direct oral anticoagulants.

Dr. Werring noted that these reports do not add anything to the overall risk/benefit of the vaccine, as they are only describing three cases. “While VITT is very serious, the benefit of the vaccine still outweighs its risks,” he said. “Around 40% of patients hospitalized with COVID-19 experience some sort of thrombosis and about 1.5% have an ischemic stroke. Whereas latest figures from the U.K. estimate the incidence of VITT with the AstraZeneca vaccine of 1 in 50,000 to 1 in 100,000.

“Our report doesn’t suggest that VITT is more common than these latest figures estimate, but we are just drawing attention to an alternative presentation,” he added.  
 

Three cases

The first patient in the current case series, a woman in her 30s, experienced an intermittent headache on the right side and around her eyes 6 days after the vaccine. Five days later, she awoke feeling drowsy and with weakness to her left face, arm, and leg.

Imaging revealed a blocked right middle cerebral artery with brain infarction and clots in the right portal vein. She underwent brain surgery to reduce the pressure in her skull, plasma removal and replacement, and received the anticoagulant fondaparinux, but she still unfortunately died.

The second patient, a woman in her late 30s, presented with headache, confusion, weakness in her left arm, and loss of vision on the left side 12 days after having received the vaccine. Imaging showed occlusion of both carotid arteries, as well as pulmonary embolism and a left cerebral venous sinus thrombosis.  

Her platelet count increased following plasma removal and replacement and intravenous corticosteroids, and her condition improved after fondaparinux treatment.

The third patient, a man in his early 40s, presented 3 weeks after receiving his vaccination with problems speaking. Imaging showed a clot in the left middle cerebral artery, but there was no evidence of clots in the cerebral venous sinuses. He received a platelet and plasma transfusion, and fondaparinux, and remains stable.
 

High index of suspicion required

In a linked commentary, Hugh Markus, PhD, FRCP, professor of stroke medicine at the University of Cambridge, United Kingdom, wrote: “This report emphasizes that the immune mediated coagulopathy can also cause arterial thrombosis, including ischemic stroke, although venous thrombosis and especially cerebral venous sinus thrombosis appear more frequent.

“During the current period of COVID vaccination, a high index of suspicion is required to identify thrombotic episodes following vaccination,” he added. “However, it is important to remember that these side effects are rare and much less common than both cerebral venous thrombosis and ischemic stroke associated with COVID-19 infection itself.”
 

Risk/benefit unaltered

Several experts who commented on these reports for the Science Media Centre all agreed with Dr. Werring and Dr. Markus that these reports do not alter the current risk/benefit estimates with the vaccine.

Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who sits on the U.K.’s Medicines and Healthcare Products Regulatory Agency’s Pharmacovigilance Expert Advisory Group, said: “The picture regarding the rare syndrome of blood clots combined with low platelet counts associated with the AstraZeneca vaccine is becoming clearer. Until now, the cases described have tended to involve clots in veins such as cerebral vein thrombosis. In this series of three case reports, we now have some evidence that the types of blood vessels affected include arteries as well as veins.”  

“It’s important to stress that such cases remain very rare, and it’s certainly much rarer in people who have had the AstraZeneca vaccine than it is in people affected by COVID-19 itself,” Dr. Douglas emphasized.

“The description of the cases suggests the patients involved presented with the same kind of symptoms as already described in cases involving cerebral vein thrombosis, and they don’t suggest patients need to be on the alert for anything different,” he added.

“However, the emergence of details like this will help guide health professionals who may be faced with similar cases in future; the sooner such cases are recognized, the more chance they will quickly receive the right kind of treatment, hopefully leading to better outcomes.”

Will Lester, MBChB, PhD, consultant hematologist, University Hospitals Birmingham NHS Foundation Trust, said: “VITT remains a rare complication, and patients with a history of thrombosis, including stroke, should not consider themselves to be at any higher risk of this type of rare thrombosis after vaccination, and COVID infection itself is a significant risk for stroke and other types of thrombosis.”

Many countries have paused use of the AstraZeneca vaccine because of its link to the VITT syndrome or restricted its use to older people as the VITT reaction appears to be slightly more common in younger people. In the United Kingdom, the current recommendation is that individuals under 40 years of age should be offered an alternative to the AstraZeneca vaccine where possible.

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

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

Some nonsleepy patients with coronary artery disease and obstructive sleep apnea (OSA) may receive cardiovascular benefit from continuous positive airway pressure (CPAP) therapy, according to a post hoc analysis of the RICCADSA clinical trial. That study found no benefit among patients overall, but the new analysis found that patients whose heart rate increases (delta heart rate, or dHR) more than average during apnea or hypopnea experienced fewer cardiovascular or cerebrovascular events during apnea or hypopnea when treated with CPAP.

Although RICCADSA showed no benefit, an analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and the Sleep Heart Health Study (SHHS) cohorts found that elevated pulse rate response to respiratory events was associated with greater risk of cardiovascular disease (CVD) morbidity and mortality. But the effect was seen only in nonsleepy patients. “We hypothesized that pulse rate response to apneas would predict which patients with OSA may most benefit from CPAP treatment. Now, our study suggests that there is, in fact, a subgroup of nonsleepy patients with OSA for whom CPAP could provide a reduction in risk, specifically those with a higher pulse rate response to their respiratory events,” Ali Azarbarzin, PhD, said in an interview.

Dr. Azarbarzin presented the study at the American Thoracic Society’s virtual international conference (Abstract A1103). He is in the division of sleep and circadian disorders at Brigham and Women’s Hospital, and is assistant professor of medicine at Harvard Medical School, both in Boston.

The study is in line with recent efforts to subgroup OSA patients to determine which are at higher risk of cardiovascular events and other complications, and which are most likely to respond to treatment, according to Esra Tasali, MD, of the University of Chicago, who moderated the session where the study was presented. “The field is really urgently in need of coming up with new methods, and I think this study is getting a handle on that,” said Dr. Tasali in an interview.

“I think that this is really pointing toward a new area that the whole (sleep field) is moving toward, which is better phenotyping of sleep apnea so that we can come up with more personalized treatments,” said Dr. Tasali.

The patients who appeared to gain a cardiovascular benefit from CPAP represented about 16% of trial participants. Dr. Azarbarzin refrained from making clinical recommendations, citing the need for more data. The team next plans to reproduce the findings in additional, larger trials such as the SAVE and ISAACC trials. “Ultimately, our goal is to confirm our findings in a future randomized controlled trial of CPAP by enrolling participants based on their pulse rate response,” said Dr. Azarbarzin.

The RICCADSA study was a single center randomized, controlled trial with 226 patients with coronary artery disease and OSA who were randomized to CPAP or no CPAP treatment. In the overall population, CPAP treatment was not associated with a statistically significant change in repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality (hazard ratio [HR], 0.79; P = .435). That study assumed that the effect of OSA on CVD is similar across all subgroups of dHR.

The mean increase in heart rate was 7.1 beats per minute (BPM; standard deviation, 3.7). Each standard deviation increase in dHR was linked to greater CVD risk (HR, 1.45; P = .029). For each standard deviation decrease in dHR, treatment with CPAP decreased the CVD risk (HR, 0.54; P = .043).

For patients with a low dHR of 4 BPM, the hazard ratio for CVD was 0.8 with no CPAP treatment and 1.2 for CPAP treatment. For those at the mean value of 7 BPM, the HRs were 1.1 and 0.9 respectively. For those with a high dHR, (10 BPM), the hazard ratio was 1.6 without treatment and 0.7 with CPAP.

“We modeled delta heart rate interaction with CPAP, which was significant. What this means is that for someone with a mean delta heart rate of 7 beats per minute, the risk reduction (with CPAP) is similar to what RICCADSA reported. But if you look at those with high delta heart rate, the risk reduction was significantly larger. It was actually a more than 50% reduction of risk with CPAP treatment,” said Dr. Azarbarzin.

Dr. Azarbarzin has consulted for Somnifix and Apnimed and has received grants from Somnifix. Dr. Tasali has no relevant financial disclosures.

Despite the huge challenges of COVID-19, including a drop in patient visits, cardiologists reported an average increase in income in 2020 and remain among the top earners in medicine, according to the 2021 Medscape Cardiologist Compensation Report.

Although 46% of cardiologists reported some decline in compensation, average cardiologist income was $459,000 in 2020 – up from $438,000 in 2019.

Cardiologist pay is the third highest of all specialties in the overall 2021 Medscape Physician Compensation Report, which covers U.S. physicians as a whole and almost 18,000 physicians in 29 specialties. 

Only plastic surgeons ($526,000) and orthopedists ($511,000) earned more than cardiologists in 2020.

On average among cardiologists, self-employment yields a somewhat higher paycheck than does being employed ($477,000 vs. $450,000).

Just like in last year’s report, nearly two-thirds (61%) of cardiologists overall say they feel fairly compensated.

The average incentive bonus payment for cardiologists in 2020 was 14% of total salary, about the same as last year. Two-thirds of cardiologists who earn an incentive bonus achieve more than three-quarters of their potential annual payment, up from 55% the prior year.
 

COVID challenges and the road back

The vast majority (92%) of cardiologists who saw a drop in income last year cited COVID-related issues such as job loss, working fewer hours, and seeing fewer patients.

Close to half (48%) of cardiologists who suffered financial or practice-related ill effects as a result of the pandemic expect their income to return to normal this year; 38% believe it will take 2 to 3 years. Notably, 45% of physicians overall said the pandemic did not cause them financial or practice-related harm.

Physician work hours generally declined for at least some time during the pandemic – and some physicians were furloughed – but most are now working about the same number of hours they did prior to COVID-19.

Cardiologists are back working an average of 57 hours per week. Perhaps not surprising, intensivists, infectious disease physicians, and public health/preventive medicine physicians are pulling longer hours now, about 6 or 7 more per week than before.

Although working about the same number of hours per week now as they did before the pandemic, physicians overall are typically seeing fewer patients because of time spent on medical office safety protocols, answering COVID-19–related questions and other factors.

Cardiologists are seeing an average decline in weekly patient visits of about 6% – from 77 to 72 patients. Pediatricians are experiencing the largest average declines – from 78 patients per week prior to 64 now, an 18% drop.

Among self-employed cardiologists, 43% believe that a drop in patient volume of up to one-quarter is permanent.
 

Most cardiologists remain happy at work

Despite COVID-19 and other professional challenges, most cardiologists (and physicians overall) continue to find their work rewarding.

Cardiologists say the most rewarding aspect of their profession is “being good at what I do/finding answers and diagnoses” (27%), followed by relationships with and gratitude from patients (26%), making the world a better place (23%) and making good money at a job they like (12%). A few cited pride in their profession (6%) and teaching (2%). These figures are in line with last year’s responses.

The most challenging part of practicing cardiology is having so many rules and regulations (22%), followed by having to work long hours (16%), working with electronic health records (13%), trouble getting fair reimbursement (11%), danger/risk associated with treating COVID-19 patients (11%), dealing with difficult patients (8%) and worry about being sued (7%).

Bureaucratic tasks continue to be a burden for physicians in all specialties. On average, cardiologists spend 17.4 hours per week on paperwork and administration, similar to last year (16.9 hours per week) and to physicians overall (16.3 hours).

Despite the challenges, 86% of cardiologists said they would choose medicine again, and 92% would choose cardiology again, about the same as last year.

Most cardiologists (83%) plan to keep Medicare and/or Medicaid patients; only 1% say they won’t take new Medicare or Medicaid patients; and 16% are undecided.

Thirty-nine percent of cardiologists plan to participate in the Merit-based Incentive Payment System (MIPS) in 2021. 

“The stakes of the Quality Payment Program – the program that incorporates MIPS – are high, with a 9% penalty applied to all Medicare reimbursement for failure to participate,” said Elizabeth Woodcock, MBA, CPC, president of physician practice consulting firm Woodcock & Associates, Atlanta.

“With margins already slim, most physicians can’t afford this massive penalty. It makes sense to protect your revenue by complying with at least the bare minimum,” she noted.

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

Despite the huge challenges of COVID-19, including a drop in patient visits, cardiologists reported an average increase in income in 2020 and remain among the top earners in medicine, according to the 2021 Medscape Cardiologist Compensation Report.

Although 46% of cardiologists reported some decline in compensation, average cardiologist income was $459,000 in 2020 – up from $438,000 in 2019.

Cardiologist pay is the third highest of all specialties in the overall 2021 Medscape Physician Compensation Report, which covers U.S. physicians as a whole and almost 18,000 physicians in 29 specialties. 

Only plastic surgeons ($526,000) and orthopedists ($511,000) earned more than cardiologists in 2020.

On average among cardiologists, self-employment yields a somewhat higher paycheck than does being employed ($477,000 vs. $450,000).

Just like in last year’s report, nearly two-thirds (61%) of cardiologists overall say they feel fairly compensated.

The average incentive bonus payment for cardiologists in 2020 was 14% of total salary, about the same as last year. Two-thirds of cardiologists who earn an incentive bonus achieve more than three-quarters of their potential annual payment, up from 55% the prior year.
 

COVID challenges and the road back

The vast majority (92%) of cardiologists who saw a drop in income last year cited COVID-related issues such as job loss, working fewer hours, and seeing fewer patients.

Close to half (48%) of cardiologists who suffered financial or practice-related ill effects as a result of the pandemic expect their income to return to normal this year; 38% believe it will take 2 to 3 years. Notably, 45% of physicians overall said the pandemic did not cause them financial or practice-related harm.

Physician work hours generally declined for at least some time during the pandemic – and some physicians were furloughed – but most are now working about the same number of hours they did prior to COVID-19.

Cardiologists are back working an average of 57 hours per week. Perhaps not surprising, intensivists, infectious disease physicians, and public health/preventive medicine physicians are pulling longer hours now, about 6 or 7 more per week than before.

Although working about the same number of hours per week now as they did before the pandemic, physicians overall are typically seeing fewer patients because of time spent on medical office safety protocols, answering COVID-19–related questions and other factors.

Cardiologists are seeing an average decline in weekly patient visits of about 6% – from 77 to 72 patients. Pediatricians are experiencing the largest average declines – from 78 patients per week prior to 64 now, an 18% drop.

Among self-employed cardiologists, 43% believe that a drop in patient volume of up to one-quarter is permanent.
 

Most cardiologists remain happy at work

Despite COVID-19 and other professional challenges, most cardiologists (and physicians overall) continue to find their work rewarding.

Cardiologists say the most rewarding aspect of their profession is “being good at what I do/finding answers and diagnoses” (27%), followed by relationships with and gratitude from patients (26%), making the world a better place (23%) and making good money at a job they like (12%). A few cited pride in their profession (6%) and teaching (2%). These figures are in line with last year’s responses.

The most challenging part of practicing cardiology is having so many rules and regulations (22%), followed by having to work long hours (16%), working with electronic health records (13%), trouble getting fair reimbursement (11%), danger/risk associated with treating COVID-19 patients (11%), dealing with difficult patients (8%) and worry about being sued (7%).

Bureaucratic tasks continue to be a burden for physicians in all specialties. On average, cardiologists spend 17.4 hours per week on paperwork and administration, similar to last year (16.9 hours per week) and to physicians overall (16.3 hours).

Despite the challenges, 86% of cardiologists said they would choose medicine again, and 92% would choose cardiology again, about the same as last year.

Most cardiologists (83%) plan to keep Medicare and/or Medicaid patients; only 1% say they won’t take new Medicare or Medicaid patients; and 16% are undecided.

Thirty-nine percent of cardiologists plan to participate in the Merit-based Incentive Payment System (MIPS) in 2021. 

“The stakes of the Quality Payment Program – the program that incorporates MIPS – are high, with a 9% penalty applied to all Medicare reimbursement for failure to participate,” said Elizabeth Woodcock, MBA, CPC, president of physician practice consulting firm Woodcock & Associates, Atlanta.

“With margins already slim, most physicians can’t afford this massive penalty. It makes sense to protect your revenue by complying with at least the bare minimum,” she noted.

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

Despite the huge challenges of COVID-19, including a drop in patient visits, cardiologists reported an average increase in income in 2020 and remain among the top earners in medicine, according to the 2021 Medscape Cardiologist Compensation Report.

Although 46% of cardiologists reported some decline in compensation, average cardiologist income was $459,000 in 2020 – up from $438,000 in 2019.

Cardiologist pay is the third highest of all specialties in the overall 2021 Medscape Physician Compensation Report, which covers U.S. physicians as a whole and almost 18,000 physicians in 29 specialties. 

Only plastic surgeons ($526,000) and orthopedists ($511,000) earned more than cardiologists in 2020.

On average among cardiologists, self-employment yields a somewhat higher paycheck than does being employed ($477,000 vs. $450,000).

Just like in last year’s report, nearly two-thirds (61%) of cardiologists overall say they feel fairly compensated.

The average incentive bonus payment for cardiologists in 2020 was 14% of total salary, about the same as last year. Two-thirds of cardiologists who earn an incentive bonus achieve more than three-quarters of their potential annual payment, up from 55% the prior year.
 

COVID challenges and the road back

The vast majority (92%) of cardiologists who saw a drop in income last year cited COVID-related issues such as job loss, working fewer hours, and seeing fewer patients.

Close to half (48%) of cardiologists who suffered financial or practice-related ill effects as a result of the pandemic expect their income to return to normal this year; 38% believe it will take 2 to 3 years. Notably, 45% of physicians overall said the pandemic did not cause them financial or practice-related harm.

Physician work hours generally declined for at least some time during the pandemic – and some physicians were furloughed – but most are now working about the same number of hours they did prior to COVID-19.

Cardiologists are back working an average of 57 hours per week. Perhaps not surprising, intensivists, infectious disease physicians, and public health/preventive medicine physicians are pulling longer hours now, about 6 or 7 more per week than before.

Although working about the same number of hours per week now as they did before the pandemic, physicians overall are typically seeing fewer patients because of time spent on medical office safety protocols, answering COVID-19–related questions and other factors.

Cardiologists are seeing an average decline in weekly patient visits of about 6% – from 77 to 72 patients. Pediatricians are experiencing the largest average declines – from 78 patients per week prior to 64 now, an 18% drop.

Among self-employed cardiologists, 43% believe that a drop in patient volume of up to one-quarter is permanent.
 

Most cardiologists remain happy at work

Despite COVID-19 and other professional challenges, most cardiologists (and physicians overall) continue to find their work rewarding.

Cardiologists say the most rewarding aspect of their profession is “being good at what I do/finding answers and diagnoses” (27%), followed by relationships with and gratitude from patients (26%), making the world a better place (23%) and making good money at a job they like (12%). A few cited pride in their profession (6%) and teaching (2%). These figures are in line with last year’s responses.

The most challenging part of practicing cardiology is having so many rules and regulations (22%), followed by having to work long hours (16%), working with electronic health records (13%), trouble getting fair reimbursement (11%), danger/risk associated with treating COVID-19 patients (11%), dealing with difficult patients (8%) and worry about being sued (7%).

Bureaucratic tasks continue to be a burden for physicians in all specialties. On average, cardiologists spend 17.4 hours per week on paperwork and administration, similar to last year (16.9 hours per week) and to physicians overall (16.3 hours).

Despite the challenges, 86% of cardiologists said they would choose medicine again, and 92% would choose cardiology again, about the same as last year.

Most cardiologists (83%) plan to keep Medicare and/or Medicaid patients; only 1% say they won’t take new Medicare or Medicaid patients; and 16% are undecided.

Thirty-nine percent of cardiologists plan to participate in the Merit-based Incentive Payment System (MIPS) in 2021. 

“The stakes of the Quality Payment Program – the program that incorporates MIPS – are high, with a 9% penalty applied to all Medicare reimbursement for failure to participate,” said Elizabeth Woodcock, MBA, CPC, president of physician practice consulting firm Woodcock & Associates, Atlanta.

“With margins already slim, most physicians can’t afford this massive penalty. It makes sense to protect your revenue by complying with at least the bare minimum,” she noted.

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

Cardiovascular disease risk is associated with alcohol intake in general, but variations in risk exist with levels of intake, based on data from a genetic-based assessment of more than 300,000 individuals.

alenkadr/Thinkstock

Previous studies have identified the “J-shaped model” of alcohol intake and cardiovascular disease, Kiran J. Biddinger of the Broad Institute, Cambridge, Mass., and colleagues said. The J-shaped model suggests that light alcohol intake, defined as one to two drinks per day, appears to reduce cardiovascular disease risk, while heavy alcohol intake, defined as about five drinks per day, increases cardiovascular disease risk, Mr. Biddenger said. However, most studies of the association between alcohol and cardiovascular disease risk are observational, and subject to confounders such as the impact of healthy lifestyle behaviors.

To better assess causality, the researchers used a genetics technique known as Mendelian randomization.

“Some individuals are genetically predisposed to drink more alcohol than others, based on the random allocation of alleles,” he explained. This genetic risk should not be associated with confounding variables such as vegetable consumption or physical activity.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association, the researchers analyzed genetic and lifestyle data from 371,463 participants in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom. The researchers used traditional and nonlinear genetic approaches to assess causality between alcohol consumption and cardiovascular disease.

Overall, study participants averaged 9.2 drinks per week. A total of 121,708 (32.8%) had hypertension, and 27,667 (7.5%) had coronary artery disease. The researchers found that individuals who consumed light to moderate amounts of alcohol also lived healthier lifestyles, and had a lower body mass index and higher levels of physical activity than did those who abstained from alcohol. Light to moderate drinkers also had higher vegetable consumption, lower red meat consumption, were less likely to smoke, and had higher self-reported overall health ratings, compared with abstainers.

The researchers then applied Mendelian randomization analyses, creating a genetic proxy and finding that individuals who were predisposed to drink more alcohol had a higher risk of cardiovascular disease.

Traditional and nonlinear Mendelian randomization using quadratic associations showed consistently increased risk of cardiovascular disease with increased alcohol consumption, and this risk increased dramatically for the heaviest drinkers. Compared with individuals who abstained, alcohol consumption of 7, 14, 21, and 28 drinks per week was associated, respectively, with 1.2-, 1.7-, 3.4-, and 8.9-fold odds of hypertension, and 1.2-, 2.3-, 6.2-, and 25.9-fold odds of coronary artery disease.

Notably, an increase of one standard deviation in genetic predisposition for alcohol consumption was associated with a 1.28-fold increase in hypertension, as well as significantly increased risk of coronary artery disease (odds ratio, 1.38), MI (OR, 1.37), stroke (OR, 1.26), heart failure (OR, 1.34), and atrial fibrillation (OR, 1.24).

The study findings were limited by several factors, including the inability to detect specific benefits associated with moderate alcohol consumption. However, the results suggest that, although all amounts of alcohol intake convey some increase in cardiovascular disease risk, “recommendations around alcohol use should reflect this nuanced relationship,” Mr. Biddinger said.

Distinctive study design supports association

Studies examining the association of alcohol consumption with cardiovascular (CVD) outcomes have been mostly observational in nature because of ethical considerations, Anna Kucharska-Newton, PhD, of the University of North Carolina at Chapel Hill, said in an interview. “Results of those studies have not been conclusive, and more research is needed. This study takes advantage of the ‘natural experiment’ of the randomized distribution of genetic variants associated with alcohol consumption,” said Dr. Kucharska-Newton, who served as moderator for the session at the meeting when the study was presented. “This method is similar to a randomized clinical trial and as such is less subject to confounding and potential reverse causality than an observational study..

“The findings confirm data from previous studies, including published data based on the UK Biobank study and the FinnGen registry of genetic data,” said Dr. Kucharska-Newton. “Findings from that study are largely supportive, suggesting that alcohol intake is associated with increased risk of coronary artery disease, an association that is sustained following adjustment for smoking.

“What the present study adds is an elegant presentation of the nonlinearity in that association. However, in contrast to the earlier study that included participants who reported drinking 1-2 drinks per week, Mr. Biddinger and colleagues examined effects among those drinking 7-28 drinks per week, making generalization to light to moderate drinkers [the majority] difficult,” she noted.

As for clinical implications, “assessment of habitual drinking is an important element in routine clinical care.” Dr. Kucharska-Newton noted. “Alcohol intake of seven or more drinks per week is associated exponentially with increased risk of coronary artery disease and, as other data suggest, increased levels of CVD risk factors. Therefore, CVD risk factor control is of particular importance in this population.

“Additional research in populations of ancestry other than White European is very much needed,” Dr. Kucharska-Newton emphasized. “Replication of the analyses presented by Mr. Biddinger and colleagues in different cohorts would strengthen inferences from this study. Extension of study findings to clinically manifest CVD would provide more relevant take-home messages. However, prior studies, based on Mendelian randomization protocols, suggest that adjustment for lifestyle factors attenuates the association of alcohol intake with adverse clinical CVD outcomes.”

Mr. Biddinger had no financial conflicts to disclose, but several coauthors disclosed relationships with companies including Novartis, Regeneron, Bayer, Quest Diagnostics, Corvidia, Pfizer, Verve Therapeutics, and Medgenome. Dr. Kucharska-Newton had no financial conflicts to disclose.

Cardiovascular disease risk is associated with alcohol intake in general, but variations in risk exist with levels of intake, based on data from a genetic-based assessment of more than 300,000 individuals.

alenkadr/Thinkstock

Previous studies have identified the “J-shaped model” of alcohol intake and cardiovascular disease, Kiran J. Biddinger of the Broad Institute, Cambridge, Mass., and colleagues said. The J-shaped model suggests that light alcohol intake, defined as one to two drinks per day, appears to reduce cardiovascular disease risk, while heavy alcohol intake, defined as about five drinks per day, increases cardiovascular disease risk, Mr. Biddenger said. However, most studies of the association between alcohol and cardiovascular disease risk are observational, and subject to confounders such as the impact of healthy lifestyle behaviors.

To better assess causality, the researchers used a genetics technique known as Mendelian randomization.

“Some individuals are genetically predisposed to drink more alcohol than others, based on the random allocation of alleles,” he explained. This genetic risk should not be associated with confounding variables such as vegetable consumption or physical activity.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association, the researchers analyzed genetic and lifestyle data from 371,463 participants in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom. The researchers used traditional and nonlinear genetic approaches to assess causality between alcohol consumption and cardiovascular disease.

Overall, study participants averaged 9.2 drinks per week. A total of 121,708 (32.8%) had hypertension, and 27,667 (7.5%) had coronary artery disease. The researchers found that individuals who consumed light to moderate amounts of alcohol also lived healthier lifestyles, and had a lower body mass index and higher levels of physical activity than did those who abstained from alcohol. Light to moderate drinkers also had higher vegetable consumption, lower red meat consumption, were less likely to smoke, and had higher self-reported overall health ratings, compared with abstainers.

The researchers then applied Mendelian randomization analyses, creating a genetic proxy and finding that individuals who were predisposed to drink more alcohol had a higher risk of cardiovascular disease.

Traditional and nonlinear Mendelian randomization using quadratic associations showed consistently increased risk of cardiovascular disease with increased alcohol consumption, and this risk increased dramatically for the heaviest drinkers. Compared with individuals who abstained, alcohol consumption of 7, 14, 21, and 28 drinks per week was associated, respectively, with 1.2-, 1.7-, 3.4-, and 8.9-fold odds of hypertension, and 1.2-, 2.3-, 6.2-, and 25.9-fold odds of coronary artery disease.

Notably, an increase of one standard deviation in genetic predisposition for alcohol consumption was associated with a 1.28-fold increase in hypertension, as well as significantly increased risk of coronary artery disease (odds ratio, 1.38), MI (OR, 1.37), stroke (OR, 1.26), heart failure (OR, 1.34), and atrial fibrillation (OR, 1.24).

The study findings were limited by several factors, including the inability to detect specific benefits associated with moderate alcohol consumption. However, the results suggest that, although all amounts of alcohol intake convey some increase in cardiovascular disease risk, “recommendations around alcohol use should reflect this nuanced relationship,” Mr. Biddinger said.

Distinctive study design supports association

Studies examining the association of alcohol consumption with cardiovascular (CVD) outcomes have been mostly observational in nature because of ethical considerations, Anna Kucharska-Newton, PhD, of the University of North Carolina at Chapel Hill, said in an interview. “Results of those studies have not been conclusive, and more research is needed. This study takes advantage of the ‘natural experiment’ of the randomized distribution of genetic variants associated with alcohol consumption,” said Dr. Kucharska-Newton, who served as moderator for the session at the meeting when the study was presented. “This method is similar to a randomized clinical trial and as such is less subject to confounding and potential reverse causality than an observational study..

“The findings confirm data from previous studies, including published data based on the UK Biobank study and the FinnGen registry of genetic data,” said Dr. Kucharska-Newton. “Findings from that study are largely supportive, suggesting that alcohol intake is associated with increased risk of coronary artery disease, an association that is sustained following adjustment for smoking.

“What the present study adds is an elegant presentation of the nonlinearity in that association. However, in contrast to the earlier study that included participants who reported drinking 1-2 drinks per week, Mr. Biddinger and colleagues examined effects among those drinking 7-28 drinks per week, making generalization to light to moderate drinkers [the majority] difficult,” she noted.

As for clinical implications, “assessment of habitual drinking is an important element in routine clinical care.” Dr. Kucharska-Newton noted. “Alcohol intake of seven or more drinks per week is associated exponentially with increased risk of coronary artery disease and, as other data suggest, increased levels of CVD risk factors. Therefore, CVD risk factor control is of particular importance in this population.

“Additional research in populations of ancestry other than White European is very much needed,” Dr. Kucharska-Newton emphasized. “Replication of the analyses presented by Mr. Biddinger and colleagues in different cohorts would strengthen inferences from this study. Extension of study findings to clinically manifest CVD would provide more relevant take-home messages. However, prior studies, based on Mendelian randomization protocols, suggest that adjustment for lifestyle factors attenuates the association of alcohol intake with adverse clinical CVD outcomes.”

Mr. Biddinger had no financial conflicts to disclose, but several coauthors disclosed relationships with companies including Novartis, Regeneron, Bayer, Quest Diagnostics, Corvidia, Pfizer, Verve Therapeutics, and Medgenome. Dr. Kucharska-Newton had no financial conflicts to disclose.

Cardiovascular disease risk is associated with alcohol intake in general, but variations in risk exist with levels of intake, based on data from a genetic-based assessment of more than 300,000 individuals.

alenkadr/Thinkstock

Previous studies have identified the “J-shaped model” of alcohol intake and cardiovascular disease, Kiran J. Biddinger of the Broad Institute, Cambridge, Mass., and colleagues said. The J-shaped model suggests that light alcohol intake, defined as one to two drinks per day, appears to reduce cardiovascular disease risk, while heavy alcohol intake, defined as about five drinks per day, increases cardiovascular disease risk, Mr. Biddenger said. However, most studies of the association between alcohol and cardiovascular disease risk are observational, and subject to confounders such as the impact of healthy lifestyle behaviors.

To better assess causality, the researchers used a genetics technique known as Mendelian randomization.

“Some individuals are genetically predisposed to drink more alcohol than others, based on the random allocation of alleles,” he explained. This genetic risk should not be associated with confounding variables such as vegetable consumption or physical activity.

In a study presented at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting, sponsored by the American Heart Association, the researchers analyzed genetic and lifestyle data from 371,463 participants in the U.K. Biobank, a population-based study of more than 500,000 individuals in the United Kingdom. The researchers used traditional and nonlinear genetic approaches to assess causality between alcohol consumption and cardiovascular disease.

Overall, study participants averaged 9.2 drinks per week. A total of 121,708 (32.8%) had hypertension, and 27,667 (7.5%) had coronary artery disease. The researchers found that individuals who consumed light to moderate amounts of alcohol also lived healthier lifestyles, and had a lower body mass index and higher levels of physical activity than did those who abstained from alcohol. Light to moderate drinkers also had higher vegetable consumption, lower red meat consumption, were less likely to smoke, and had higher self-reported overall health ratings, compared with abstainers.

The researchers then applied Mendelian randomization analyses, creating a genetic proxy and finding that individuals who were predisposed to drink more alcohol had a higher risk of cardiovascular disease.

Traditional and nonlinear Mendelian randomization using quadratic associations showed consistently increased risk of cardiovascular disease with increased alcohol consumption, and this risk increased dramatically for the heaviest drinkers. Compared with individuals who abstained, alcohol consumption of 7, 14, 21, and 28 drinks per week was associated, respectively, with 1.2-, 1.7-, 3.4-, and 8.9-fold odds of hypertension, and 1.2-, 2.3-, 6.2-, and 25.9-fold odds of coronary artery disease.

Notably, an increase of one standard deviation in genetic predisposition for alcohol consumption was associated with a 1.28-fold increase in hypertension, as well as significantly increased risk of coronary artery disease (odds ratio, 1.38), MI (OR, 1.37), stroke (OR, 1.26), heart failure (OR, 1.34), and atrial fibrillation (OR, 1.24).

The study findings were limited by several factors, including the inability to detect specific benefits associated with moderate alcohol consumption. However, the results suggest that, although all amounts of alcohol intake convey some increase in cardiovascular disease risk, “recommendations around alcohol use should reflect this nuanced relationship,” Mr. Biddinger said.

Distinctive study design supports association

Studies examining the association of alcohol consumption with cardiovascular (CVD) outcomes have been mostly observational in nature because of ethical considerations, Anna Kucharska-Newton, PhD, of the University of North Carolina at Chapel Hill, said in an interview. “Results of those studies have not been conclusive, and more research is needed. This study takes advantage of the ‘natural experiment’ of the randomized distribution of genetic variants associated with alcohol consumption,” said Dr. Kucharska-Newton, who served as moderator for the session at the meeting when the study was presented. “This method is similar to a randomized clinical trial and as such is less subject to confounding and potential reverse causality than an observational study..

“The findings confirm data from previous studies, including published data based on the UK Biobank study and the FinnGen registry of genetic data,” said Dr. Kucharska-Newton. “Findings from that study are largely supportive, suggesting that alcohol intake is associated with increased risk of coronary artery disease, an association that is sustained following adjustment for smoking.

“What the present study adds is an elegant presentation of the nonlinearity in that association. However, in contrast to the earlier study that included participants who reported drinking 1-2 drinks per week, Mr. Biddinger and colleagues examined effects among those drinking 7-28 drinks per week, making generalization to light to moderate drinkers [the majority] difficult,” she noted.

As for clinical implications, “assessment of habitual drinking is an important element in routine clinical care.” Dr. Kucharska-Newton noted. “Alcohol intake of seven or more drinks per week is associated exponentially with increased risk of coronary artery disease and, as other data suggest, increased levels of CVD risk factors. Therefore, CVD risk factor control is of particular importance in this population.

“Additional research in populations of ancestry other than White European is very much needed,” Dr. Kucharska-Newton emphasized. “Replication of the analyses presented by Mr. Biddinger and colleagues in different cohorts would strengthen inferences from this study. Extension of study findings to clinically manifest CVD would provide more relevant take-home messages. However, prior studies, based on Mendelian randomization protocols, suggest that adjustment for lifestyle factors attenuates the association of alcohol intake with adverse clinical CVD outcomes.”

Mr. Biddinger had no financial conflicts to disclose, but several coauthors disclosed relationships with companies including Novartis, Regeneron, Bayer, Quest Diagnostics, Corvidia, Pfizer, Verve Therapeutics, and Medgenome. Dr. Kucharska-Newton had no financial conflicts to disclose.

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

Adversity in early life – whether preterm birth or socioeconomic disadvantage in childhood – accelerates aging, according to two recent studies, but underlying mechanisms remain unclear, and methods of investigation continue to evolve.

While one study used an established epigenetic clock to measure biological age among adults with extremely low birth weight, the other showcased a relatively new tool to measure pace of biological aging in disadvantaged children, suggesting that the metric may one day serve as a real-time measure of interventional efficacy.

These findings build upon previous studies that have demonstrated a correlation between biological age, also known as methylation age, and an increased risk of health problems later in life, according to Daniel A. Notterman, MD, professor of molecular biology at Princeton (N.J.) University.

“Finding that a person’s methylation age is greater than their chronological age has been taken as evidence of increased ‘biological age’ and perhaps a tendency to greater future morbidity,” Dr. Notterman wrote in a Pediatrics editorial. “Indeed, methylation age is advanced in association with a number of childhood and midlife adversities as well as morbidities such as atherosclerosis, cancer, and obesity.”
 

Extremely low birth weight associated with faster aging in men

For some individuals, accelerated biological aging begins at birth, or even in utero, according to Ryan J. Van Lieshout, MD, PhD, Canada Research Chair in the Perinatal Programming of Mental Disorders and the Albert Einstein/Irving Zucker Chair in Neuroscience at McMaster University, Hamilton, Ont., and colleagues.

The investigators conducted a study involving 45 extremely low birth weight (ELBW) survivors and 49 individuals born at normal birth weight. All participants were drawn from a longitudinal study conducted between 1977 and 1982 that assessed advances in neonatal intensive care. Controls were recruited at 8 years of age and matched with ELBW survivors based on family socioeconomic status, sex, and age. Follow-up continued through adulthood, allowing for the present trial to compare data from ages 8, 30, and 35.

Using samples of buccal epithelial cells, the investigators measured biological age with the Horvath epigenetic clock, the most commonly used tool of its kind, which measures cytosine-5 methylation at 353 cytosine-phosphate-guanine sites. Results were adjusted for a variety of covariates, such as smoking status, body mass index, number of chronic health conditions, and others.

Between groups, ELBW survivors trended toward older biological age, compared with adults born at normal birth weight (29.0 vs. 27.9 years), a difference that was not statistically significant. Further analysis, however, showed a significant sex-based difference between groups: Male survivors of ELBW, in adulthood, were almost 5 years biologically older than men born at normal birth weight (31.4 vs. 26.9 years; P = .01).

“[W]e provide preliminary evidence of a new link between ELBW and accelerated biological aging among men,” the investigators concluded.

In an accompanying editorial, Pam Factor-Litvak, PhD, vice chair of epidemiology at Columbia University, New York, wrote, “The findings are intriguing and open many questions for further study.”

Dr. Factor-Litvak noted that it remains unclear whether differences in biological aging were present at birth.

“[D]ifferences would provide evidence that accelerated aging begins during the in utero period, perhaps because of maternal undernutrition, stress, or another exposure,” Dr. Factor-Litvak wrote. “[R]eductions in chronic stress levels, which may begin for neonates with ELBW in utero and in the first hours of life, may provide an opportunity for interventions,” she added.

According to Calvin J. Hobel, MD, professor of pediatrics at Cedars-Sinai and professor of obstetrics and gynecology at University of California, Los Angeles, who has been studying preterm birth for more than 40 years, interventions may need to begin even earlier.

Measuring the impact of socioeconomic status on biological aging, now in real-time

A second study, by Laurel Raffington, PhD, of the University of Texas at Austin, and colleagues, evaluated the relationship between socioeconomic disadvantage in childhood and pace of biological aging.

To do so, they used the DunedinPoAm DNA methylation algorithm, a relatively new tool that was developed by analyzing changes in organ system integrity over time among adults with the same chronological age.

“Whereas epigenetic clocks quantify the amount of aging that has already occurred up to the time of measurement, DunedinPoAm quantifies how fast an individual is aging,” Dr. Raffington and colleagues wrote. “In other words, whereas epigenetic clocks tell you what time it is, pace-of-aging measures tell you how fast the clock is ticking.”

The investigators measured pace of aging in 600 children and adolescents (8-18 years of age) from the Texas Twin Project, “an ongoing longitudinal study that includes the collection of salivary samples.” The final dataset included 457 participants who identified as White, 77 who identified as Latinx, and 61 who identified as both White and Latinx.

The investigators evaluated pace of aging compared with family-level and neighborhood-level socioeconomic status, and tested for confounding by tobacco exposure, BMI, and pubertal development.

This analysis revealed that children experiencing socioeconomic disadvantage were aging more quickly than their peers, in terms of both family-level and neighborhood-level inequity (both levels, r = 0.18; P = .001).

Children who identified as Latinx aged faster than did those who identified as White only or White and Latinx, “consistent with higher levels of disadvantage in this group,” the investigators wrote. “Thus, our findings are consistent with observations that racial and/or ethnic socioeconomic disparities are an important contributor to racial and/or ethnic disparities in health.”

Higher BMI, greater tobacco exposure, and more advanced pubertal development were also associated with more rapid aging. After adjustment for these covariates, however, the significant correlation between socioeconomic disadvantage and rapid aging remained, the investigators noted.

“Our results suggest that salivary DNA methylation measures of pace of aging may provide a surrogate or intermediate endpoint for understanding the health impacts of [childhood] interventions,” the investigators concluded. “Such applications may prove particularly useful for evaluating the effectiveness of health-promoting interventions in at-risk groups.”

Still, more work is needed to understand exactly how socioeconomic disadvantage is associated with accelerated aging.

“Ultimately, not only longitudinal repeated-measures studies but also natural experiment studies and randomized controlled trials of social programs are needed to establish causal effects of social disadvantage on DunedinPoAm-measured pace of aging and to establish DunedinPoAm as a mediator of the process through which childhood disadvantage leads to aging-related health conditions,” the investigators wrote.

In his editorial, Dr. Notterman emphasized this point.

“[I]t is worth remembering that associations with either methylation age or pace of aging and health or longevity may represent the effect of an exposure on both the measure and the outcome of interest rather than a causal pathway that runs from the exposure (low socioeconomic status, adversity) to health outcome (i.e., cancer, vascular disease),” he wrote.

Paul Chung, MD, professor and chair of health systems science at Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, Calif., and adjunct professor at the University of California, Los Angeles, called the findings “preliminary,” but noted that confirmation through further research could “fill in some really important gaps.

“Right now, to some degree, we’re at a little bit of an impasse,” Dr. Chung said.

Adverse childhood experiences are “associated very strongly” with mental and physical health issues, Dr. Chung said, “but we don’t know exactly why, and because of that, it’s really hard to come up with social policy solutions that aren’t anything but extremely sort of blunt-ended. We just say, ‘Well, I guess you gotta fix everything.’ And it’s a hard place to be, I think, in the field.”

Although the present study doesn’t resolve this issue, Dr. Chung suggested that the findings “really open the door to a lot of really exciting research that could have a lot of impacts on practice and policy.”

“Sometimes the only way to get people to pay attention enough to generate the level of excitement that would allow you to even do these sorts of studies ... is to generate some initial exploratory data that makes people perk up their ears, and makes people go, ‘Hey, wow, maybe we should be looking into this.’ ”

The study by Dr. Raffington and colleagues was funded by the National Institutes of Health and the Jacobs Foundation, with additional support from the German Research Foundation, Russell Sage Foundation Biology and Social Science Grant, the Canadian Institute for Advanced Research Child and Brain Development Network, and others. The study by Dr. Lieshout and colleagues was supported by Canadian Institutes of Health Research. Dr. Factor-Litvak and Dr. Notterman reported funding from the National Institutes of Health. All of the investigators and interviewees reported no conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

The first randomized controlled trial to compare specific temperatures for therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest showed no differences in major outcomes, according to a single-center, double-blind study.

In the CAPITAL-CHILL trial, cooling temperatures of 31° C and 34° C were compared to explore the hypothesis that a lower temperature would improve major outcomes, explained Michel Le May, MD.

No differences for the primary composite outcome of all-cause mortality or poor neurologic outcome at 180 days were observed, he reported at the annual scientific sessions of the American College of Cardiology.

The study was completed over a period of almost 7 years in patients presumed to have had an out-of-hospital cardiac arrest and who were unconscious when they reached a center affiliated with the Ottawa Heart Institute, where Dr. Le May directs the regional STEMI (ST-elevation myocardial infarction) program. The initial rhythm at the time of the cardiac arrest was not an entry criterion.

Of 389 patients enrolled, the intention-to-treat analysis included 184 randomized to a cooling temperature of 31° C group and 183 to a temperature of 34° C. The assigned target temperature, reached with an endovascular device, was known only by the managing nurses.
 

31° C and 34° C are equivalent

There was a small numerical disadvantage for the lower temperature assignment, but none reached statistical significance. This was true of the primary outcome (48.4% vs. 45.4% for the higher temperature) and its components of mortality (43.5% vs. 41.0%) and poor neurologic outcome (4.9% vs. 4.4%). Poor neurologic outcome was defined as a Disability Rating Scale score of greater than 5.

Deaths were most common in the early part of the 180-day follow-up in both arms. On a Kaplan-Meier survival graph, Dr. Le May showed curves that he characterized as “almost superimposable.”

There were no significant differences for any subgroup stratifications, such as age 75 years or older versus younger, males versus females, presence versus absence or an initial shockable rhythm, percutaneous coronary intervention (PCI) within 24 hours versus later, and STEMI versus non-STEMI. In these analyses, the higher temperature was associated with a potential trend for benefit among females and those with a shockable rhythm.

There was no signal for a difference in neurologic outcomes on the Disability Rating Scale or the Modified Rankin Scale. On the latter, for example, 46% of those in the 31° C group and 44% of these in the 34° C group had a score of four or greater at the end of follow-up.

The baseline characteristics of the two groups were similar. About 80% were male; the average age was roughly 62 years. More than 80% of the cardiac arrests were witnessed with CPR being administered by bystanders in nearly 70%. Nearly 40% had a STEMI.

Interventions were similar. Almost all patients underwent coronary angiography, of which nearly 60% received a percutaneous coronary intervention. More than 50% received a stent. The time from arrest to randomization was slightly longer in the 31° C group (228 vs. 204 minutes). The time to balloon inflation from arrival at the cardiac center was also slightly longer (73 vs. 60 minutes).

There was a trend for an increased rate of seizures in the 31° C group (12.5% vs. 7.1%; P = .08), but other secondary outcomes, including pneumonia (67.8% vs. 63.4%), renal replacement therapy (9.2% vs. 9.3%), and stroke (4.4% vs. 1.6%), were similar in the 31° C and 34° C groups, respectively.

Bleeding, whether measured by transfusion (19.6% vs. 22.4%) or TIMI major bleed (23.4% vs. 19.7%) were similar in the 31° C and 34° C groups, respectively. Thrombosis, whether measured by stent thrombosis (1.2% vs. 2.2%) or deep venous thrombosis (11.4% vs. 10.9%) were similar in these two groups, respectively.

The length of stay in the cardiac intensive care unit was significantly greater in the 31° C group (10 vs. 7 days; P = .004). Some of this increased length of stay can be attributed to the longer rewarming process required for the greater cooling, according to Dr. Le May, but he acknowledged that it is not clear this provides a full explanation.
 

More trials like CAPITAL-CHILL needed

The validity of these findings is supported by several strengths of the methodology, according to Jeanne E. Poole, MD, director of the arrhythmia service and electrophysiology laboratory, University of Washington, Seattle. This includes the reliance of an endovascular device, which can accelerate the time to the target temperature and assure the precision with which it is reached and maintained.

Dr. Poole did note that many of the primary and secondary measures, including the rates of stroke, seizures, and major bleeds, even though not significantly different, favored the higher temperature. The slightly longer door-to-balloon times might have been a factor. For the higher rate of pneumonia in the 31° C group, she questioned whether the longer period of ventilation linked to a longer period of rewarming might have been a factor.

However, Dr. Poole praised the CAPITAL-CHILL trial for drawing attention to a group of patients for whom survival rates remain “dismally low.” She indicated that these types of high-level trials are needed to look for strategies to improve outcomes.

Dr. Le May and Dr. Poole report no potential conflicts of interest.

There is no safe amount of alcohol consumption for the brain; even moderate drinking adversely affects brain structure and function, according a British study of more 25,000 adults.

“This is one of the largest studies of alcohol and brain health to date,” Anya Topiwala, DPhil, University of Oxford (England), told this news organization.

“There have been previous claims the relationship between alcohol and brain health are J-shaped (ie., small amounts are protective), but we formally tested this and did not find it to be the case. In fact, we found that any level of alcohol was associated with poorer brain health, compared to no alcohol,” Dr. Topiwala added.

The study, which has not yet been peer reviewed, was published online May 12 in MedRxiv.
 

Global impact on the brain

Using the UK Biobank, the researchers evaluated brain health on the basis of structural and functional brain MRI measures in 25,378 adults. Participants provided detailed information on their alcohol intake. The cohort included 691 never-drinkers, 617 former drinkers, and 24,069 current drinkers.

Median alcohol intake was 13.5 units (102 g) weekly. Almost half of the sample (48.2%) were drinking above current UK low-risk guidelines (14 units, 112 g weekly), but few were heavy drinkers (>50 units, 400 g weekly).

After adjusting for all known potential confounders and multiple comparisons, a higher volume of alcohol consumed per week was associated with lower gray matter in “almost all areas of the brain,” Dr. Topiwala said in an interview.

Alcohol consumption accounted for up to 0.8% of gray matter volume variance. “The size of the effect is small, albeit greater than any other modifiable risk factor. These brain changes have been previously linked to aging, poorer performance on memory changes, and dementia,” Dr. Topiwala said.

Widespread negative associations were also found between drinking alcohol and all the measures of white matter integrity that were assessed. There was a significant positive association between alcohol consumption and resting-state functional connectivity.

Higher blood pressure and body mass index “steepened” the negative associations between alcohol and brain health, and binge drinking had additive negative effects on brain structure beyond the absolute volume consumed.

There was no evidence that the risk for alcohol-related brain harm differs according to the type of alcohol consumed (wine, beer, or spirits).

A key limitation of the study is that the study population from the UK Biobank represents a sample that is healthier, better educated, and less deprived and is characterized by less ethnic diversity than the general population. “As with any observational study, we cannot infer causality from association,” the authors note.

What remains unclear, they say, is the duration of drinking needed to cause an effect on the brain. It may be that vulnerability is increased during periods of life in which dynamic brain changes occur, such as adolescence and older age.

They also note that some studies of alcohol-dependent individuals have suggested that at least some brain damage is reversible upon abstinence. Whether that is true for moderate drinkers is unknown.

On the basis of their findings, there is “no safe dose of alcohol for the brain,” Dr. Topiwala and colleagues conclude. They suggest that current low-risk drinking guidelines be revisited to take account of brain effects.
 

Experts weigh in

Several experts weighed in on the study in a statement from the nonprofit UK Science Media Center.

Paul Matthews, MD, head of the department of brain sciences, Imperial College London, noted that this “carefully performed preliminary report extends our earlier UK Dementia Research Institute study of a smaller group from same UK Biobank population also showing that even moderate drinking is associated with greater atrophy of the brain, as well as injury to the heart and liver.”

Dr. Matthews said the investigators’ conclusion that there is no safe threshold below which alcohol consumption has no toxic effects “echoes our own. We join with them in suggesting that current public health guidelines concerning alcohol consumption may need to be revisited.”

Rebecca Dewey, PhD, research fellow in neuroimaging, University of Nottingham (England), cautioned that “the degree to which very small changes in brain volume are harmful” is unknown.

“While there was no threshold under which alcohol consumption did not cause changes in the brain, there may a degree of brain volume difference that is irrelevant to brain health. We don’t know what these people’s brains looked like before they drank alcohol, so the brain may have learned to cope/compensate,” Dewey said.

Sadie Boniface, PhD, head of research at the Institute of Alcohol Studies and visiting researcher at King’s College London, said, “While we can’t yet say for sure whether there is ‘no safe level’ of alcohol regarding brain health at the moment, it has been known for decades that heavy drinking is bad for brain health.

“We also shouldn’t forget alcohol affects all parts of the body and there are multiple health risks. For example, it is already known there is ‘no safe level’ of alcohol consumption for the seven types of cancer caused by alcohol, as identified by the UK chief medical officers,” Dr. Boniface said.

The study was supported in part by the Wellcome Trust, Li Ka Shing Center for Health Information and Discovery, the National Institutes of Health, and the UK Medical Research Council. Dr. Topiwala, Dr. Boniface, Dr. Dewey, and Dr. Matthews have disclosed no relevant financial relationships.

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

There is no safe amount of alcohol consumption for the brain; even moderate drinking adversely affects brain structure and function, according a British study of more 25,000 adults.

“This is one of the largest studies of alcohol and brain health to date,” Anya Topiwala, DPhil, University of Oxford (England), told this news organization.

“There have been previous claims the relationship between alcohol and brain health are J-shaped (ie., small amounts are protective), but we formally tested this and did not find it to be the case. In fact, we found that any level of alcohol was associated with poorer brain health, compared to no alcohol,” Dr. Topiwala added.

The study, which has not yet been peer reviewed, was published online May 12 in MedRxiv.
 

Global impact on the brain

Using the UK Biobank, the researchers evaluated brain health on the basis of structural and functional brain MRI measures in 25,378 adults. Participants provided detailed information on their alcohol intake. The cohort included 691 never-drinkers, 617 former drinkers, and 24,069 current drinkers.

Median alcohol intake was 13.5 units (102 g) weekly. Almost half of the sample (48.2%) were drinking above current UK low-risk guidelines (14 units, 112 g weekly), but few were heavy drinkers (>50 units, 400 g weekly).

After adjusting for all known potential confounders and multiple comparisons, a higher volume of alcohol consumed per week was associated with lower gray matter in “almost all areas of the brain,” Dr. Topiwala said in an interview.

Alcohol consumption accounted for up to 0.8% of gray matter volume variance. “The size of the effect is small, albeit greater than any other modifiable risk factor. These brain changes have been previously linked to aging, poorer performance on memory changes, and dementia,” Dr. Topiwala said.

Widespread negative associations were also found between drinking alcohol and all the measures of white matter integrity that were assessed. There was a significant positive association between alcohol consumption and resting-state functional connectivity.

Higher blood pressure and body mass index “steepened” the negative associations between alcohol and brain health, and binge drinking had additive negative effects on brain structure beyond the absolute volume consumed.

There was no evidence that the risk for alcohol-related brain harm differs according to the type of alcohol consumed (wine, beer, or spirits).

A key limitation of the study is that the study population from the UK Biobank represents a sample that is healthier, better educated, and less deprived and is characterized by less ethnic diversity than the general population. “As with any observational study, we cannot infer causality from association,” the authors note.

What remains unclear, they say, is the duration of drinking needed to cause an effect on the brain. It may be that vulnerability is increased during periods of life in which dynamic brain changes occur, such as adolescence and older age.

They also note that some studies of alcohol-dependent individuals have suggested that at least some brain damage is reversible upon abstinence. Whether that is true for moderate drinkers is unknown.

On the basis of their findings, there is “no safe dose of alcohol for the brain,” Dr. Topiwala and colleagues conclude. They suggest that current low-risk drinking guidelines be revisited to take account of brain effects.
 

Experts weigh in

Several experts weighed in on the study in a statement from the nonprofit UK Science Media Center.

Paul Matthews, MD, head of the department of brain sciences, Imperial College London, noted that this “carefully performed preliminary report extends our earlier UK Dementia Research Institute study of a smaller group from same UK Biobank population also showing that even moderate drinking is associated with greater atrophy of the brain, as well as injury to the heart and liver.”

Dr. Matthews said the investigators’ conclusion that there is no safe threshold below which alcohol consumption has no toxic effects “echoes our own. We join with them in suggesting that current public health guidelines concerning alcohol consumption may need to be revisited.”

Rebecca Dewey, PhD, research fellow in neuroimaging, University of Nottingham (England), cautioned that “the degree to which very small changes in brain volume are harmful” is unknown.

“While there was no threshold under which alcohol consumption did not cause changes in the brain, there may a degree of brain volume difference that is irrelevant to brain health. We don’t know what these people’s brains looked like before they drank alcohol, so the brain may have learned to cope/compensate,” Dewey said.

Sadie Boniface, PhD, head of research at the Institute of Alcohol Studies and visiting researcher at King’s College London, said, “While we can’t yet say for sure whether there is ‘no safe level’ of alcohol regarding brain health at the moment, it has been known for decades that heavy drinking is bad for brain health.

“We also shouldn’t forget alcohol affects all parts of the body and there are multiple health risks. For example, it is already known there is ‘no safe level’ of alcohol consumption for the seven types of cancer caused by alcohol, as identified by the UK chief medical officers,” Dr. Boniface said.

The study was supported in part by the Wellcome Trust, Li Ka Shing Center for Health Information and Discovery, the National Institutes of Health, and the UK Medical Research Council. Dr. Topiwala, Dr. Boniface, Dr. Dewey, and Dr. Matthews have disclosed no relevant financial relationships.

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

There is no safe amount of alcohol consumption for the brain; even moderate drinking adversely affects brain structure and function, according a British study of more 25,000 adults.

“This is one of the largest studies of alcohol and brain health to date,” Anya Topiwala, DPhil, University of Oxford (England), told this news organization.

“There have been previous claims the relationship between alcohol and brain health are J-shaped (ie., small amounts are protective), but we formally tested this and did not find it to be the case. In fact, we found that any level of alcohol was associated with poorer brain health, compared to no alcohol,” Dr. Topiwala added.

The study, which has not yet been peer reviewed, was published online May 12 in MedRxiv.
 

Global impact on the brain

Using the UK Biobank, the researchers evaluated brain health on the basis of structural and functional brain MRI measures in 25,378 adults. Participants provided detailed information on their alcohol intake. The cohort included 691 never-drinkers, 617 former drinkers, and 24,069 current drinkers.

Median alcohol intake was 13.5 units (102 g) weekly. Almost half of the sample (48.2%) were drinking above current UK low-risk guidelines (14 units, 112 g weekly), but few were heavy drinkers (>50 units, 400 g weekly).

After adjusting for all known potential confounders and multiple comparisons, a higher volume of alcohol consumed per week was associated with lower gray matter in “almost all areas of the brain,” Dr. Topiwala said in an interview.

Alcohol consumption accounted for up to 0.8% of gray matter volume variance. “The size of the effect is small, albeit greater than any other modifiable risk factor. These brain changes have been previously linked to aging, poorer performance on memory changes, and dementia,” Dr. Topiwala said.

Widespread negative associations were also found between drinking alcohol and all the measures of white matter integrity that were assessed. There was a significant positive association between alcohol consumption and resting-state functional connectivity.

Higher blood pressure and body mass index “steepened” the negative associations between alcohol and brain health, and binge drinking had additive negative effects on brain structure beyond the absolute volume consumed.

There was no evidence that the risk for alcohol-related brain harm differs according to the type of alcohol consumed (wine, beer, or spirits).

A key limitation of the study is that the study population from the UK Biobank represents a sample that is healthier, better educated, and less deprived and is characterized by less ethnic diversity than the general population. “As with any observational study, we cannot infer causality from association,” the authors note.

What remains unclear, they say, is the duration of drinking needed to cause an effect on the brain. It may be that vulnerability is increased during periods of life in which dynamic brain changes occur, such as adolescence and older age.

They also note that some studies of alcohol-dependent individuals have suggested that at least some brain damage is reversible upon abstinence. Whether that is true for moderate drinkers is unknown.

On the basis of their findings, there is “no safe dose of alcohol for the brain,” Dr. Topiwala and colleagues conclude. They suggest that current low-risk drinking guidelines be revisited to take account of brain effects.
 

Experts weigh in

Several experts weighed in on the study in a statement from the nonprofit UK Science Media Center.

Paul Matthews, MD, head of the department of brain sciences, Imperial College London, noted that this “carefully performed preliminary report extends our earlier UK Dementia Research Institute study of a smaller group from same UK Biobank population also showing that even moderate drinking is associated with greater atrophy of the brain, as well as injury to the heart and liver.”

Dr. Matthews said the investigators’ conclusion that there is no safe threshold below which alcohol consumption has no toxic effects “echoes our own. We join with them in suggesting that current public health guidelines concerning alcohol consumption may need to be revisited.”

Rebecca Dewey, PhD, research fellow in neuroimaging, University of Nottingham (England), cautioned that “the degree to which very small changes in brain volume are harmful” is unknown.

“While there was no threshold under which alcohol consumption did not cause changes in the brain, there may a degree of brain volume difference that is irrelevant to brain health. We don’t know what these people’s brains looked like before they drank alcohol, so the brain may have learned to cope/compensate,” Dewey said.

Sadie Boniface, PhD, head of research at the Institute of Alcohol Studies and visiting researcher at King’s College London, said, “While we can’t yet say for sure whether there is ‘no safe level’ of alcohol regarding brain health at the moment, it has been known for decades that heavy drinking is bad for brain health.

“We also shouldn’t forget alcohol affects all parts of the body and there are multiple health risks. For example, it is already known there is ‘no safe level’ of alcohol consumption for the seven types of cancer caused by alcohol, as identified by the UK chief medical officers,” Dr. Boniface said.

The study was supported in part by the Wellcome Trust, Li Ka Shing Center for Health Information and Discovery, the National Institutes of Health, and the UK Medical Research Council. Dr. Topiwala, Dr. Boniface, Dr. Dewey, and Dr. Matthews have disclosed no relevant financial relationships.

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