Neurology

A novel formulation containing meloxicam and rizatriptan provides effective pain relief for patients with migraine, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.

In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.

Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.

“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

Acute treatments needed

For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.

The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.

Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.

In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.

The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.

The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.

Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
 

Reduced pain progression

Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).

Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).

The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).

In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).

AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).

The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.

“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
 

Improved adherence?

Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.

AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.

“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.

The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.

Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
 

Uncertain therapeutic advantage

Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.

“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.

It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.

In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.

For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.

Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.

“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.

“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.

The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.

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

A novel formulation containing meloxicam and rizatriptan provides effective pain relief for patients with migraine, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.

In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.

Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.

“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

Acute treatments needed

For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.

The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.

Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.

In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.

The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.

The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.

Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
 

Reduced pain progression

Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).

Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).

The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).

In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).

AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).

The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.

“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
 

Improved adherence?

Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.

AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.

“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.

The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.

Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
 

Uncertain therapeutic advantage

Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.

“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.

It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.

In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.

For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.

Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.

“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.

“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.

The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.

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

A novel formulation containing meloxicam and rizatriptan provides effective pain relief for patients with migraine, new research suggests. Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patients’ most bothersome symptom (MBS) compared with placebo.

In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.

Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.

“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” said study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine at Dartmouth, Hanover, N.H. “That is why the whole is greater than the sum of the parts,” Dr. Tepper added.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

Acute treatments needed

For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.

The search for optimal acute treatments is therefore “really important for patients,” Dr. Tepper noted.

Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene-related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.

In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.

The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.

The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom and freedom from pain progression, functional disability, and use of rescue medication.

Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.
 

Reduced pain progression

Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).

Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).

The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs. 9.6%; P = .013).

In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, versus 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).

AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, versus 27.7% of the placebo group (P < .001).

The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, versus 2.1%; the rate of dizziness was 2.9%, versus 1.4%; and the rate of paresthesia was 2.1%, versus 0%. There were no serious AEs.

“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Dr. Tepper. “It’s not dramatically different for dizziness.”
 

Improved adherence?

Meloxicam is generally used not as an acute medication but for prevention, Dr. Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.

AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.

“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Dr. Tepper.

The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly. “We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Dr. Tepper said.

Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply. “It’s a big adherence issue,” said Dr. Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”
 

Uncertain therapeutic advantage

Commenting on the findings, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, Burlington, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.

“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Dr. Shapiro, who was not involved with the research.

It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.

In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Dr. Shapiro.

For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, versus 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs. 16.3% for the AXS-07 trial) were comparable.

Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, versus 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs. 12.6% for AXS-07).
The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, versus 7% and 5%, respectively for participants in the two sumatriptan–naproxen sodium trials.

“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Dr. Shapiro.

“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.

The study was funded by Axsome Therapeutics. Dr. Tepper is a consultant to Axsome Therapeutics. Dr. Shapiro has previously performed research consulting for Lilly and Lundbeck.

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

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

There’s abundant evidence linking higher alcohol intake levels to greater stroke risk and, separately, increasing risk for new-onset atrial fibrillation (AFib). Less settled is whether moderate to heavy drinking worsens the risk for stroke in patients already in AFib and whether giving up alcohol can attenuate that risk. A new observational study suggests the answer to both questions is yes.

The risk for ischemic stroke was only around 1% over about 5 years in a Korean nationwide cohort of almost 98,000 patients with new-onset AFib. About half the patients followed were nondrinkers, as they had been before the study, 13% became abstinent soon after their AFib diagnosis, and 36% were currently drinkers.

But stroke risk went up about 30% with “moderate” current alcohol intake, compared with no intake, and by more than 40% for current drinkers reporting “heavy” alcohol intake, researchers found in an adjusted analysis.

However, abstainers who had mild to moderate alcohol-intake levels before their AFib diagnosis “had a similar risk of ischemic stroke as nondrinkers,” write the authors, led by So-Ryoung Lee, MD, PhD, and colleagues, Seoul National University Hospital, Republic of Korea, in their report published June 7 in the European Heart Journal. In a secondary analysis, binge drinking was also independently associated with risk for ischemic stroke.

The findings suggest that “alcohol abstinence after the diagnosis of AFib could reduce the risk of ischemic stroke,” they conclude. “Lifestyle interventions, including attention to alcohol consumption, should be encouraged as part of a comprehensive approach in the management of patients with a new diagnosis of AFib” for lowering the risk for stroke and other clinical outcomes.

“These results are pretty comparable to those obtained in the more general population,” David Conen, MD, MPH, not connected to the analysis, told this news organization.

In the study’s population with new-onset AFib, there is an alcohol-dependent risk for stroke “that goes up with increasing alcohol intake, which is more or less similar to that found without atrial fibrillation in previous studies,” said Dr. Conen, from the Population Health Research Institute, McMaster University, Hamilton, Ont.

The study, “which overall I think is very well done,” he said, is noteworthy for also suggesting that binge drinking, which was scrutinized in a secondary analysis, appeared independently to worsen the risk for stroke in its AFib population.

Dr. Conen said the observed 1% overall risk for stroke was very similar to the rate he and his colleagues saw in a recent combined analysis of two European cohorts with AFib that was usually longer standing; the median was 3 years. That analysis, in contrast, showed no significant association between increasing levels of alcohol intake and risk for stroke or systemic embolism.

However, “our confidence limits did not exclude the possibility of a small to moderate association,” he said. Given that, and the current study from Korea, there might indeed be “a weak association between alcohol consumption and stroke” in patients with AFib.

“Their results are just more precise because of the larger sample size. That’s why they were able to show those associations,” said Dr. Conen, who was senior author on the earlier report, which covered a pooled analysis of 3,852 patients with AFib in the BEAT-AF and SWISS-AF cohort studies. It was published January 25 in CMAJ, with lead author Philipp Reddiess, MD, Cardiovascular Research Institute Basel, Switzerland.

The two published studies contrast in other ways that are worth noting and together suggest the stroke rate might have been 1% in both by chance, Dr. Conen said. “The populations were pretty different.”

In the earlier study, for example, the overwhelmingly European patients had more comorbidities and had been in AFib for much longer; their mean age was 71 years; and 84% were on oral anticoagulation (OAC).

In contrast, the Korean cohort averaged 61 years in age and only about 24% were taking oral anticoagulants. Given their distribution of CHA2DS2-VASc scores and mean score of 2.3, more than twice as many should have been on OAC, Dr. Conen speculated. “Even if you take into account that some patients may have contraindications, this is clearly an underanticoagulated population.”

The European cohort might have been “a little bit more representative because atrial fibrillation is a disease of the elderly,” Dr. Conen said, but “the Korean paper has the advantage of being a population-based study.”

It involved 97,869 patients from a Korean national data base who were newly diagnosed with AFib from 2010 to 2016. Of the total, 49,781 (51%) were continuously nondrinkers before and after their diagnosis; 12,789 (13%) abstained from alcohol only after their AFib diagnosis; and 35,299 (36%) were drinkers during the follow-up, either because they continued to drink or newly started after their diagnosis.

Of the cohort, 3,120 were diagnosed with new ischemic stroke over a follow-up of 310,926 person-years, for a rate of 1 per 100 person-years.

The adjusted hazard ratio (HR) for ischemic stroke over a 5-year follow-up, compared with nondrinkers, was:

• 1.127 (95% confidence interval, 1.003-1.266) among abstainers
• 1.280 (95% CI, 1.166-1.405) for current drinkers

The corresponding HR, compared with current drinkers, was:

• 0.781 (95% CI, 0.712-0.858) for nondrinkers
• 0.880 (95% CI, 0.782-0.990) among abstainers

No significant interactions with ischemic stroke risk were observed in groups by sex, age, CHA2DS2-VASc score, or smoking status. The risk rose consistently with current drinking levels.

The overall stroke rate of 1% per year is “very low,” and “the absolute differences are small, even though there is a clear significant trend from nondrinking to drinking,” Dr. Conen said.

However, “the difference becomes more sizable when you compare heavy drinking to abstinence.”

Dr. Lee reports no conflicts of interest; disclosures for the other authors are in their report. Dr. Conen reports receiving speaker fees from Servier Canada; disclosures for the other authors are in their report.

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

It is safe for patients with migraine to receive any of the COVID-19 vaccines without concern about the vaccination interfering with their migraine medications or the medications reducing an immune response to the vaccine, according to a presentation at the American Headache Society’s 2021 annual meeting.

Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.

“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.

Common questions

The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.

In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.

Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.

“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”

She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.

The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.

During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.

“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.

Migraine or vaccine reaction?

Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.

TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.

So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.

In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.

“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.

The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”

For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”

Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.

Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.

“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.

Continue to vaccinate

“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.

“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”

Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.

Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.

It is safe for patients with migraine to receive any of the COVID-19 vaccines without concern about the vaccination interfering with their migraine medications or the medications reducing an immune response to the vaccine, according to a presentation at the American Headache Society’s 2021 annual meeting.

Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.

“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.

Common questions

The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.

In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.

Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.

“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”

She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.

The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.

During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.

“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.

Migraine or vaccine reaction?

Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.

TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.

So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.

In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.

“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.

The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”

For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”

Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.

Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.

“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.

Continue to vaccinate

“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.

“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”

Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.

Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.

It is safe for patients with migraine to receive any of the COVID-19 vaccines without concern about the vaccination interfering with their migraine medications or the medications reducing an immune response to the vaccine, according to a presentation at the American Headache Society’s 2021 annual meeting.

Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.

“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.

Common questions

The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.

In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.

Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.

“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”

She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.

The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.

During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.

“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.

Migraine or vaccine reaction?

Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.

TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.

So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.

In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.

“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.

The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”

For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”

Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.

Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.

“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.

Continue to vaccinate

“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.

“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”

Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.

Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.

THE CASES

Winston S* is a 23-year-old man referred by a psychiatrist colleague for primary care. He works delivering papers in the early morning hours and spends his day alone in his apartment mainly eating frozen pizza. He has worked solitary jobs his entire life and says he prefers it that way. His answers to questions lack emotion. He doesn’t seem to have any friends or regular contact with family. He follows the medical advice he receives but can’t seem to get out of the house to exercise or socialize. His psychiatrist was treating him with a selective serotonin reuptake inhibitor for depression when he was referred.

Denise L* is a 37-year-old woman who transferred to your practice because she says the previous practice’s office manager was disrespectful and the doctor did not listen to her. She has been “very appreciative” of you and your “well-run office.” You have addressed her fibromyalgia and she has shared several personal details about her life. In the following weeks, you receive several phone calls and messages from her. At a follow-up visit, she asks questions about your family and seems agitated when you hesitate to answer. She questions whether you remember details of her history. She pushes, “Did you remember that, doctor?” She also mentions that your front desk staff seems rude to her. 

Ruth B* is an 82-year-old woman whose blood pressure measured in your office is 176/94 mm Hg. When you recommend starting a medication and getting blood tests, she responds with a litany of fearful questions. She seems immobilized by worries about treatment and equally so about the risks of nontreatment. You can’t seem to get past the anxiety to decide on a satisfactory plan. She has to write everything down on a notepad and worries if she does not get every detail.

● How would you proceed with these patients?

* This patient’s name has been changed to protect his identity. The other 2 patients are an amalgam of patients for whom the authors have provided care.

The International Personality Disorder Examination has a 15-minute screening tool to help identify a personality disorder, regardless of cluster. According to a survey of practicing primary care physicians, as many as 15% of patient encounters can be difficult.¹ Demanding, intrusive, or angry patients who reject health care interventions are often-cited sources of these difficulties.^2,3 While it is true that patient, physician, and environmental factors may contribute to challenging interactions, some patients who are “difficult” may actually have a personality disorder that requires a distinctive approach to care. Recognizing these patients can help empower physicians to provide compassionate and effective care, reduce team angst, and minimize burnout.

❚ What qualifies as a personality disorder? A personality disorder is an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is unchanging over time, and leads to distress or impairment in social or occupational functioning.⁴ The prevalence of any personality disorder seems to have increased over the past decade from 9.1%⁴ to 12.16%.⁵ The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies personality disorders in 3 clusters—A, B, and C (TABLE⁴)—with prevalence rates at 7.23%, 5.53%, and 6.7%, respectively.⁵ The review below will focus on the distinct personality disorders exhibited by the patients described in the opening cases.

Continue to: A closer look at the clusters...

A closer look at the clusters

Cluster A disorders

Paranoid, schizoid, and schizotypal disorders are part of this cluster. These patients exhibit odd or eccentric thinking and behavior. Individuals with schizoid personality disorder, for instance, usually lack relationships and lack the desire to acquire and maintain relationships.⁴ They often organize their lives to remain isolated and will choose occupations that require little social interaction. They sometimes view themselves as observers rather than participants in their own lives.⁶

Cluster B disorders

Dramatic, overly emotional, or unpredictable thinking and behavior are characteristic of individuals who have antisocial, borderline, histrionic, or narcissistic disorders. Patients with borderline personality disorder (BPD), for example, demonstrate a longstanding pattern of instability in affect, self-image, and relationships.⁴ Patients with BPD often display extreme interpersonal hypersensitivity and make frantic efforts to avoid real or imagined abandonment. Identity disturbance, feelings of emptiness, and efforts to avoid abandonment have all been associated with increased suicide risk.⁷

In a primary care setting, such a patient may display extremely strong reactions to minor disappointments. When the physician is unavailable for a last-minute appointment or to authorize an unscheduled medication refill or to receive an after-hours phone call, the patient may become irate. The physician, who previously was idealized by the patient as “the only person who understands me,” is now devalued as “the worst doctor I’ve ever had.”⁸

Cluster C disorders

With these individuals, anxious or fearful thinking and behavior predominate. Avoidant, dependent, and obsessive-compulsive disorders are included in this cluster.

Dependent personality disorder (DPD) is characterized by a pervasive and extreme need to be taken care of. Submissive and clingy behavior and fear of separation are excessive. This patient may have difficulty making everyday decisions, being assertive, or expressing disagreement with others.⁴

Obsessive-compulsive personality disorder falls in this cluster and is typified by a pervasive preoccupation with orderliness, perfectionism, and control, at the price of flexibility and efficiency. This individual may be reluctant to get rid of sentimental objects, have rigid moral beliefs, and have significant difficulty working with others who do not follow their rules.⁴

Continue to: These clues may suggest...

If you find that encounters with a particular patient are growing increasingly difficult, consider whether the following behaviors, attitudes, and patterns of thinking are coming into play. If they are, you may want to consider using a screening tool, which we’ll discuss in a moment.

❚  Clues to cluster A disorders

• The patient has no peer relationships outside immediate family.
• The patient almost always chooses solitary activities for work and personal enjoyment.

❚  Cluster B clues

• Hypersensitivity to treatment disagreements or cancelled appointments are common (and likely experienced as rejection).
• Mood changes occur very quickly, even during a single visit.
• There is a history of many failed relationships with providers and others.
• The patient will describe an individual as both “wonderful” and “terrible” (ie, splitting) and may do so during the course of one visit.
• The patient may also split groups (eg, medical staff) by affective extremes (eg, adoration and hatred).
• The patient may hint at suicide or acts of self-harm.⁷

❚  Cluster C clues

• There is an excessive dependency on family, friends, or providers.
• Significant anxiety is experienced when the patient has to make an independent decision.
• There is a fear of relationship loss and resultant vulnerability to exploitation or abuse.
• Pervasive perfectionism makes treatment planning or course changes difficult.

• Anxiety and fear are unrelieved despite support and ample information.

Consider these screening tools

Several screening tools for personality disorders can be used to follow up on your initial clinical impressions. We also highly recommend you consider concurrent screening for substance abuse, as addiction is a common comorbidity with personality disorders.

❚ First-line treatment of personality disorders is psychotherapy; medications are mainly used for symptom management.

❚ A sampling of screening tools. The Standardised Assessment of Personality Abbreviated Scale (SAPAS)⁹ is an 8-item measure that correlates well with disorders in clusters A and C.

BPD (cluster B) has many brief scale options, including the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD).¹⁰ This 10-item questionnaire demonstrates sensitivity and specificity for BPD.

The International Personality Disorder Examination (IPDE) includes a 15-minute screening tool to help identify patients who may have any personality disorder, regardless of cluster.¹¹

Improve patient encounters with these Tx pearls

In the family medicine clinic, a collaborative primary care and behavioral health team can be extremely helpful in the diagnosis and management of patients with personality disorders.¹² First-line treatment of these disorders is psychotherapy, whereas medications are mainly used for symptom management. See Black and colleagues’ work for a thorough discussion on psychopharmacology considerations with personality disorders. ¹³

The following tips can help you to improve your interactions with patients who have personality disorders.

❚ Cluster A approaches

• Recommend treatment that respects the patient’s need for relative isolation.¹⁴

• Don’t be personally offended by your patient’s flat or disinterested affect or concrete thinking; don’t let it diminish the emotional support you provide.⁶
• Consult with a health psychologist (who has expertise in physical health conditions, brief treatments, and the medical system) to connect the patient with a long-term therapist. It is better to focus on fundamental changes, rather than employing brief behavioral techniques, for symptom relief. Patients with personality disorders tend to have better outcomes with long-term psychological care.¹⁵

❚  Cluster B approaches

• Set boundaries—eg, specific time limits for visits—and keep them.⁸
• Schedule brief, more frequent, appointments to reduce perceived feelings of abandonment.
• Coordinate plans with the entire clinic team to avoid splitting and blaming.¹⁶
• Avoid providing patients with personal information, as it may provide fodder for splitting behavior. ⁸
• Do not take things personally. Let patients “own” their own distress. These patients often take an emotional toll on the provider.¹⁶
• Engage the help of a health psychologist to reduce burnout and for more long-term continuity of care. A health psychologist who specializes in dialectical behavioral therapy to work on emotion regulation, distress tolerance, and interpersonal effectiveness would be ideal.¹⁷

Continue to: Cluster C approaches...

❚  Try to provide just 2 treatment choices to the patient with a cluster C personality disorder.

❚ Cluster C approaches

• Engage the help of family and other trusted individuals in supporting treatment plans.^18,19
• Try to provide just 2 treatment choices to the patient and reinforce his or her responsibility to help make the decision collaboratively. This step is important since it is difficult to enhance autonomy in these patients.²⁰
• Engage the help of a cognitive behavioral therapist who can work on assertiveness and problem-solving skills.¹⁹
• Be empathetic with the patient and patiently build a trusting relationship, rather than “arguing” with the patient about each specific worry.²⁰
• Make only one change at a time. Give small assignments to the ­patient, such as monitoring symptoms or reading up on their condition. These can help the patient feel more in control.²¹
• Present information in brief, clear terms. Avoid “grey areas” to reduce anxiety.²¹
• Engage a behavioral health provider to reduce rigid expectations and ideally increase feelings of self-­esteem; this has been shown to predict better treatment outcomes.²²

CASES

Mr. S displays cluster-A characteristics of schizoid personality disorder in addition to the depression he is being treated for. His physician was not put off by his flat affect and respected his limitations with social activities. Use of a stationary bike was recommended for exercise rather than walks outdoors. He also preferred phone calls to in-person encounters, so his follow-up visits were conducted by phone.

Ms. L exhibits cluster-B characteristics of BPD. You begin the tricky dance of setting limits, keeping communication clear, and not blaming yourself or others on your team for Ms. L’s feelings. You schedule regular visits with explicit time limits and discuss with your entire team how to avoid splitting. You involve a psychologist, familiar with treating BPD, who helps the patient learn positive interpersonal coping skills.

Ms. B displays cluster-C characteristics of dependent and obsessive-compulsive personality disorders. At her follow-up visit, you provide a great deal of empathy and try not to argue her out of each worry that she brings up. You make one change at a time and enlist the help of her daughter in giving her pills at home and offering reassurance. You collaborate with a cognitive behavioral therapist who works on exposing her to moderately anxiety-provoking situations/decisions. 

THE CASES

Winston S* is a 23-year-old man referred by a psychiatrist colleague for primary care. He works delivering papers in the early morning hours and spends his day alone in his apartment mainly eating frozen pizza. He has worked solitary jobs his entire life and says he prefers it that way. His answers to questions lack emotion. He doesn’t seem to have any friends or regular contact with family. He follows the medical advice he receives but can’t seem to get out of the house to exercise or socialize. His psychiatrist was treating him with a selective serotonin reuptake inhibitor for depression when he was referred.

Denise L* is a 37-year-old woman who transferred to your practice because she says the previous practice’s office manager was disrespectful and the doctor did not listen to her. She has been “very appreciative” of you and your “well-run office.” You have addressed her fibromyalgia and she has shared several personal details about her life. In the following weeks, you receive several phone calls and messages from her. At a follow-up visit, she asks questions about your family and seems agitated when you hesitate to answer. She questions whether you remember details of her history. She pushes, “Did you remember that, doctor?” She also mentions that your front desk staff seems rude to her. 

Ruth B* is an 82-year-old woman whose blood pressure measured in your office is 176/94 mm Hg. When you recommend starting a medication and getting blood tests, she responds with a litany of fearful questions. She seems immobilized by worries about treatment and equally so about the risks of nontreatment. You can’t seem to get past the anxiety to decide on a satisfactory plan. She has to write everything down on a notepad and worries if she does not get every detail.

● How would you proceed with these patients?

* This patient’s name has been changed to protect his identity. The other 2 patients are an amalgam of patients for whom the authors have provided care.

The International Personality Disorder Examination has a 15-minute screening tool to help identify a personality disorder, regardless of cluster. According to a survey of practicing primary care physicians, as many as 15% of patient encounters can be difficult.¹ Demanding, intrusive, or angry patients who reject health care interventions are often-cited sources of these difficulties.^2,3 While it is true that patient, physician, and environmental factors may contribute to challenging interactions, some patients who are “difficult” may actually have a personality disorder that requires a distinctive approach to care. Recognizing these patients can help empower physicians to provide compassionate and effective care, reduce team angst, and minimize burnout.

❚ What qualifies as a personality disorder? A personality disorder is an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is unchanging over time, and leads to distress or impairment in social or occupational functioning.⁴ The prevalence of any personality disorder seems to have increased over the past decade from 9.1%⁴ to 12.16%.⁵ The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies personality disorders in 3 clusters—A, B, and C (TABLE⁴)—with prevalence rates at 7.23%, 5.53%, and 6.7%, respectively.⁵ The review below will focus on the distinct personality disorders exhibited by the patients described in the opening cases.

Continue to: A closer look at the clusters...

A closer look at the clusters

Cluster A disorders

Paranoid, schizoid, and schizotypal disorders are part of this cluster. These patients exhibit odd or eccentric thinking and behavior. Individuals with schizoid personality disorder, for instance, usually lack relationships and lack the desire to acquire and maintain relationships.⁴ They often organize their lives to remain isolated and will choose occupations that require little social interaction. They sometimes view themselves as observers rather than participants in their own lives.⁶

Cluster B disorders

Dramatic, overly emotional, or unpredictable thinking and behavior are characteristic of individuals who have antisocial, borderline, histrionic, or narcissistic disorders. Patients with borderline personality disorder (BPD), for example, demonstrate a longstanding pattern of instability in affect, self-image, and relationships.⁴ Patients with BPD often display extreme interpersonal hypersensitivity and make frantic efforts to avoid real or imagined abandonment. Identity disturbance, feelings of emptiness, and efforts to avoid abandonment have all been associated with increased suicide risk.⁷

In a primary care setting, such a patient may display extremely strong reactions to minor disappointments. When the physician is unavailable for a last-minute appointment or to authorize an unscheduled medication refill or to receive an after-hours phone call, the patient may become irate. The physician, who previously was idealized by the patient as “the only person who understands me,” is now devalued as “the worst doctor I’ve ever had.”⁸

Cluster C disorders

With these individuals, anxious or fearful thinking and behavior predominate. Avoidant, dependent, and obsessive-compulsive disorders are included in this cluster.

Dependent personality disorder (DPD) is characterized by a pervasive and extreme need to be taken care of. Submissive and clingy behavior and fear of separation are excessive. This patient may have difficulty making everyday decisions, being assertive, or expressing disagreement with others.⁴

Obsessive-compulsive personality disorder falls in this cluster and is typified by a pervasive preoccupation with orderliness, perfectionism, and control, at the price of flexibility and efficiency. This individual may be reluctant to get rid of sentimental objects, have rigid moral beliefs, and have significant difficulty working with others who do not follow their rules.⁴

Continue to: These clues may suggest...

If you find that encounters with a particular patient are growing increasingly difficult, consider whether the following behaviors, attitudes, and patterns of thinking are coming into play. If they are, you may want to consider using a screening tool, which we’ll discuss in a moment.

❚  Clues to cluster A disorders

• The patient has no peer relationships outside immediate family.
• The patient almost always chooses solitary activities for work and personal enjoyment.

❚  Cluster B clues

• Hypersensitivity to treatment disagreements or cancelled appointments are common (and likely experienced as rejection).
• Mood changes occur very quickly, even during a single visit.
• There is a history of many failed relationships with providers and others.
• The patient will describe an individual as both “wonderful” and “terrible” (ie, splitting) and may do so during the course of one visit.
• The patient may also split groups (eg, medical staff) by affective extremes (eg, adoration and hatred).
• The patient may hint at suicide or acts of self-harm.⁷

❚  Cluster C clues

• There is an excessive dependency on family, friends, or providers.
• Significant anxiety is experienced when the patient has to make an independent decision.
• There is a fear of relationship loss and resultant vulnerability to exploitation or abuse.
• Pervasive perfectionism makes treatment planning or course changes difficult.

• Anxiety and fear are unrelieved despite support and ample information.

Consider these screening tools

Several screening tools for personality disorders can be used to follow up on your initial clinical impressions. We also highly recommend you consider concurrent screening for substance abuse, as addiction is a common comorbidity with personality disorders.

❚ First-line treatment of personality disorders is psychotherapy; medications are mainly used for symptom management.

❚ A sampling of screening tools. The Standardised Assessment of Personality Abbreviated Scale (SAPAS)⁹ is an 8-item measure that correlates well with disorders in clusters A and C.

BPD (cluster B) has many brief scale options, including the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD).¹⁰ This 10-item questionnaire demonstrates sensitivity and specificity for BPD.

The International Personality Disorder Examination (IPDE) includes a 15-minute screening tool to help identify patients who may have any personality disorder, regardless of cluster.¹¹

Improve patient encounters with these Tx pearls

In the family medicine clinic, a collaborative primary care and behavioral health team can be extremely helpful in the diagnosis and management of patients with personality disorders.¹² First-line treatment of these disorders is psychotherapy, whereas medications are mainly used for symptom management. See Black and colleagues’ work for a thorough discussion on psychopharmacology considerations with personality disorders. ¹³

The following tips can help you to improve your interactions with patients who have personality disorders.

❚ Cluster A approaches

• Recommend treatment that respects the patient’s need for relative isolation.¹⁴

• Don’t be personally offended by your patient’s flat or disinterested affect or concrete thinking; don’t let it diminish the emotional support you provide.⁶
• Consult with a health psychologist (who has expertise in physical health conditions, brief treatments, and the medical system) to connect the patient with a long-term therapist. It is better to focus on fundamental changes, rather than employing brief behavioral techniques, for symptom relief. Patients with personality disorders tend to have better outcomes with long-term psychological care.¹⁵

❚  Cluster B approaches

• Set boundaries—eg, specific time limits for visits—and keep them.⁸
• Schedule brief, more frequent, appointments to reduce perceived feelings of abandonment.
• Coordinate plans with the entire clinic team to avoid splitting and blaming.¹⁶
• Avoid providing patients with personal information, as it may provide fodder for splitting behavior. ⁸
• Do not take things personally. Let patients “own” their own distress. These patients often take an emotional toll on the provider.¹⁶
• Engage the help of a health psychologist to reduce burnout and for more long-term continuity of care. A health psychologist who specializes in dialectical behavioral therapy to work on emotion regulation, distress tolerance, and interpersonal effectiveness would be ideal.¹⁷

Continue to: Cluster C approaches...

❚  Try to provide just 2 treatment choices to the patient with a cluster C personality disorder.

❚ Cluster C approaches

• Engage the help of family and other trusted individuals in supporting treatment plans.^18,19
• Try to provide just 2 treatment choices to the patient and reinforce his or her responsibility to help make the decision collaboratively. This step is important since it is difficult to enhance autonomy in these patients.²⁰
• Engage the help of a cognitive behavioral therapist who can work on assertiveness and problem-solving skills.¹⁹
• Be empathetic with the patient and patiently build a trusting relationship, rather than “arguing” with the patient about each specific worry.²⁰
• Make only one change at a time. Give small assignments to the ­patient, such as monitoring symptoms or reading up on their condition. These can help the patient feel more in control.²¹
• Present information in brief, clear terms. Avoid “grey areas” to reduce anxiety.²¹
• Engage a behavioral health provider to reduce rigid expectations and ideally increase feelings of self-­esteem; this has been shown to predict better treatment outcomes.²²

CASES

Mr. S displays cluster-A characteristics of schizoid personality disorder in addition to the depression he is being treated for. His physician was not put off by his flat affect and respected his limitations with social activities. Use of a stationary bike was recommended for exercise rather than walks outdoors. He also preferred phone calls to in-person encounters, so his follow-up visits were conducted by phone.

Ms. L exhibits cluster-B characteristics of BPD. You begin the tricky dance of setting limits, keeping communication clear, and not blaming yourself or others on your team for Ms. L’s feelings. You schedule regular visits with explicit time limits and discuss with your entire team how to avoid splitting. You involve a psychologist, familiar with treating BPD, who helps the patient learn positive interpersonal coping skills.

Ms. B displays cluster-C characteristics of dependent and obsessive-compulsive personality disorders. At her follow-up visit, you provide a great deal of empathy and try not to argue her out of each worry that she brings up. You make one change at a time and enlist the help of her daughter in giving her pills at home and offering reassurance. You collaborate with a cognitive behavioral therapist who works on exposing her to moderately anxiety-provoking situations/decisions. 

THE CASES

Winston S* is a 23-year-old man referred by a psychiatrist colleague for primary care. He works delivering papers in the early morning hours and spends his day alone in his apartment mainly eating frozen pizza. He has worked solitary jobs his entire life and says he prefers it that way. His answers to questions lack emotion. He doesn’t seem to have any friends or regular contact with family. He follows the medical advice he receives but can’t seem to get out of the house to exercise or socialize. His psychiatrist was treating him with a selective serotonin reuptake inhibitor for depression when he was referred.

Denise L* is a 37-year-old woman who transferred to your practice because she says the previous practice’s office manager was disrespectful and the doctor did not listen to her. She has been “very appreciative” of you and your “well-run office.” You have addressed her fibromyalgia and she has shared several personal details about her life. In the following weeks, you receive several phone calls and messages from her. At a follow-up visit, she asks questions about your family and seems agitated when you hesitate to answer. She questions whether you remember details of her history. She pushes, “Did you remember that, doctor?” She also mentions that your front desk staff seems rude to her. 

Ruth B* is an 82-year-old woman whose blood pressure measured in your office is 176/94 mm Hg. When you recommend starting a medication and getting blood tests, she responds with a litany of fearful questions. She seems immobilized by worries about treatment and equally so about the risks of nontreatment. You can’t seem to get past the anxiety to decide on a satisfactory plan. She has to write everything down on a notepad and worries if she does not get every detail.

● How would you proceed with these patients?

* This patient’s name has been changed to protect his identity. The other 2 patients are an amalgam of patients for whom the authors have provided care.

The International Personality Disorder Examination has a 15-minute screening tool to help identify a personality disorder, regardless of cluster. According to a survey of practicing primary care physicians, as many as 15% of patient encounters can be difficult.¹ Demanding, intrusive, or angry patients who reject health care interventions are often-cited sources of these difficulties.^2,3 While it is true that patient, physician, and environmental factors may contribute to challenging interactions, some patients who are “difficult” may actually have a personality disorder that requires a distinctive approach to care. Recognizing these patients can help empower physicians to provide compassionate and effective care, reduce team angst, and minimize burnout.

❚ What qualifies as a personality disorder? A personality disorder is an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is unchanging over time, and leads to distress or impairment in social or occupational functioning.⁴ The prevalence of any personality disorder seems to have increased over the past decade from 9.1%⁴ to 12.16%.⁵ The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies personality disorders in 3 clusters—A, B, and C (TABLE⁴)—with prevalence rates at 7.23%, 5.53%, and 6.7%, respectively.⁵ The review below will focus on the distinct personality disorders exhibited by the patients described in the opening cases.

Continue to: A closer look at the clusters...

A closer look at the clusters

Cluster A disorders

Paranoid, schizoid, and schizotypal disorders are part of this cluster. These patients exhibit odd or eccentric thinking and behavior. Individuals with schizoid personality disorder, for instance, usually lack relationships and lack the desire to acquire and maintain relationships.⁴ They often organize their lives to remain isolated and will choose occupations that require little social interaction. They sometimes view themselves as observers rather than participants in their own lives.⁶

Cluster B disorders

Dramatic, overly emotional, or unpredictable thinking and behavior are characteristic of individuals who have antisocial, borderline, histrionic, or narcissistic disorders. Patients with borderline personality disorder (BPD), for example, demonstrate a longstanding pattern of instability in affect, self-image, and relationships.⁴ Patients with BPD often display extreme interpersonal hypersensitivity and make frantic efforts to avoid real or imagined abandonment. Identity disturbance, feelings of emptiness, and efforts to avoid abandonment have all been associated with increased suicide risk.⁷

In a primary care setting, such a patient may display extremely strong reactions to minor disappointments. When the physician is unavailable for a last-minute appointment or to authorize an unscheduled medication refill or to receive an after-hours phone call, the patient may become irate. The physician, who previously was idealized by the patient as “the only person who understands me,” is now devalued as “the worst doctor I’ve ever had.”⁸

Cluster C disorders

With these individuals, anxious or fearful thinking and behavior predominate. Avoidant, dependent, and obsessive-compulsive disorders are included in this cluster.

Dependent personality disorder (DPD) is characterized by a pervasive and extreme need to be taken care of. Submissive and clingy behavior and fear of separation are excessive. This patient may have difficulty making everyday decisions, being assertive, or expressing disagreement with others.⁴

Obsessive-compulsive personality disorder falls in this cluster and is typified by a pervasive preoccupation with orderliness, perfectionism, and control, at the price of flexibility and efficiency. This individual may be reluctant to get rid of sentimental objects, have rigid moral beliefs, and have significant difficulty working with others who do not follow their rules.⁴

Continue to: These clues may suggest...

If you find that encounters with a particular patient are growing increasingly difficult, consider whether the following behaviors, attitudes, and patterns of thinking are coming into play. If they are, you may want to consider using a screening tool, which we’ll discuss in a moment.

❚  Clues to cluster A disorders

• The patient has no peer relationships outside immediate family.
• The patient almost always chooses solitary activities for work and personal enjoyment.

❚  Cluster B clues

• Hypersensitivity to treatment disagreements or cancelled appointments are common (and likely experienced as rejection).
• Mood changes occur very quickly, even during a single visit.
• There is a history of many failed relationships with providers and others.
• The patient will describe an individual as both “wonderful” and “terrible” (ie, splitting) and may do so during the course of one visit.
• The patient may also split groups (eg, medical staff) by affective extremes (eg, adoration and hatred).
• The patient may hint at suicide or acts of self-harm.⁷

❚  Cluster C clues

• There is an excessive dependency on family, friends, or providers.
• Significant anxiety is experienced when the patient has to make an independent decision.
• There is a fear of relationship loss and resultant vulnerability to exploitation or abuse.
• Pervasive perfectionism makes treatment planning or course changes difficult.

• Anxiety and fear are unrelieved despite support and ample information.

Consider these screening tools

Several screening tools for personality disorders can be used to follow up on your initial clinical impressions. We also highly recommend you consider concurrent screening for substance abuse, as addiction is a common comorbidity with personality disorders.

❚ First-line treatment of personality disorders is psychotherapy; medications are mainly used for symptom management.

❚ A sampling of screening tools. The Standardised Assessment of Personality Abbreviated Scale (SAPAS)⁹ is an 8-item measure that correlates well with disorders in clusters A and C.

BPD (cluster B) has many brief scale options, including the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD).¹⁰ This 10-item questionnaire demonstrates sensitivity and specificity for BPD.

The International Personality Disorder Examination (IPDE) includes a 15-minute screening tool to help identify patients who may have any personality disorder, regardless of cluster.¹¹

Improve patient encounters with these Tx pearls

In the family medicine clinic, a collaborative primary care and behavioral health team can be extremely helpful in the diagnosis and management of patients with personality disorders.¹² First-line treatment of these disorders is psychotherapy, whereas medications are mainly used for symptom management. See Black and colleagues’ work for a thorough discussion on psychopharmacology considerations with personality disorders. ¹³

The following tips can help you to improve your interactions with patients who have personality disorders.

❚ Cluster A approaches

• Recommend treatment that respects the patient’s need for relative isolation.¹⁴

• Don’t be personally offended by your patient’s flat or disinterested affect or concrete thinking; don’t let it diminish the emotional support you provide.⁶
• Consult with a health psychologist (who has expertise in physical health conditions, brief treatments, and the medical system) to connect the patient with a long-term therapist. It is better to focus on fundamental changes, rather than employing brief behavioral techniques, for symptom relief. Patients with personality disorders tend to have better outcomes with long-term psychological care.¹⁵

❚  Cluster B approaches

• Set boundaries—eg, specific time limits for visits—and keep them.⁸
• Schedule brief, more frequent, appointments to reduce perceived feelings of abandonment.
• Coordinate plans with the entire clinic team to avoid splitting and blaming.¹⁶
• Avoid providing patients with personal information, as it may provide fodder for splitting behavior. ⁸
• Do not take things personally. Let patients “own” their own distress. These patients often take an emotional toll on the provider.¹⁶
• Engage the help of a health psychologist to reduce burnout and for more long-term continuity of care. A health psychologist who specializes in dialectical behavioral therapy to work on emotion regulation, distress tolerance, and interpersonal effectiveness would be ideal.¹⁷

Continue to: Cluster C approaches...

❚  Try to provide just 2 treatment choices to the patient with a cluster C personality disorder.

❚ Cluster C approaches

• Engage the help of family and other trusted individuals in supporting treatment plans.^18,19
• Try to provide just 2 treatment choices to the patient and reinforce his or her responsibility to help make the decision collaboratively. This step is important since it is difficult to enhance autonomy in these patients.²⁰
• Engage the help of a cognitive behavioral therapist who can work on assertiveness and problem-solving skills.¹⁹
• Be empathetic with the patient and patiently build a trusting relationship, rather than “arguing” with the patient about each specific worry.²⁰
• Make only one change at a time. Give small assignments to the ­patient, such as monitoring symptoms or reading up on their condition. These can help the patient feel more in control.²¹
• Present information in brief, clear terms. Avoid “grey areas” to reduce anxiety.²¹
• Engage a behavioral health provider to reduce rigid expectations and ideally increase feelings of self-­esteem; this has been shown to predict better treatment outcomes.²²

CASES

Mr. S displays cluster-A characteristics of schizoid personality disorder in addition to the depression he is being treated for. His physician was not put off by his flat affect and respected his limitations with social activities. Use of a stationary bike was recommended for exercise rather than walks outdoors. He also preferred phone calls to in-person encounters, so his follow-up visits were conducted by phone.

Ms. L exhibits cluster-B characteristics of BPD. You begin the tricky dance of setting limits, keeping communication clear, and not blaming yourself or others on your team for Ms. L’s feelings. You schedule regular visits with explicit time limits and discuss with your entire team how to avoid splitting. You involve a psychologist, familiar with treating BPD, who helps the patient learn positive interpersonal coping skills.

Ms. B displays cluster-C characteristics of dependent and obsessive-compulsive personality disorders. At her follow-up visit, you provide a great deal of empathy and try not to argue her out of each worry that she brings up. You make one change at a time and enlist the help of her daughter in giving her pills at home and offering reassurance. You collaborate with a cognitive behavioral therapist who works on exposing her to moderately anxiety-provoking situations/decisions. 

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

Antihypertensive medications that cross the blood-brain barrier (BBB) may be linked with less memory decline, compared with other drugs for high blood pressure, suggest the findings of a meta-analysis.

Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.

According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.

“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”

In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.

“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
 

Methods and results

The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.

The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.

Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.

Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).

According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.

“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.

Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).

The other cognitive measures were not significantly different between groups.
 

Clinicians may consider findings after accounting for other factors

Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.

“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.

The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.

“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”

Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.

He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.

“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”

He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.

“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
 

Exact mechanisms of action unknown

Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”

Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”

The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.

Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.

“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”

The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

Managing depression and anxiety in Parkinson’s disease should start with a review of medications and involve multidisciplinary care, according to a recent summary of evidence.

“Depression and anxiety have a complex relationship with the disease and while the exact mechanism for this association is unknown, both disturbances occur with increased prevalence across the disease course and when present earlier in life, increase the risk of PD by about twofold,” wrote Gregory M. Pontone, MD, of Johns Hopkins University, Baltimore, and colleagues.

Randomized trials to guide treatment of anxiety and depression in patients with Parkinson’s disease (PD) are limited, the researchers noted. However, data from a longitudinal study showed that PD patients whose depression remitted spontaneously or responded to treatment were able to attain a level of function similar to that of never-depressed PD patients, Dr. Pontone and colleagues said.

The researchers offered a pair of treatment algorithms to help guide clinicians in managing depression and anxiety in PD. However, a caveat to keep in mind is that “the benefit of antidepressant medications, used for depression or anxiety, can be confounded when motor symptoms are not optimally treated,” the researchers emphasized.

For depression, the researchers advised starting with some lab work; “at a minimum we suggest checking a complete blood count, metabolic panel, TSH, B12, and folate,” they noted. They recommended an antidepressant, cognitive-behavioral therapy, or both, as a first-line treatment, such as monotherapy with selective norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. They advised titrating the chosen monotherapy to a minimum effective dose over a 2- to 3-week period to assess response.

“We recommend continuing antidepressant therapy for at least 1 year based on literature in non-PD populations and anecdotal clinical experience. At 1 year, if not in remission, consider continuing treatment or augmenting to improve response,” the researchers said.

Based on the current DSM-5 criteria, up to one-third of PD patients have an unspecified anxiety disorder, the researchers said, and they recommended using anxiety rating scales to diagnose anxiety in PD. “Given the high prevalence of atypical anxiety syndromes in PD and their potential association with both motor and nonmotor symptoms of the disease, working with the neurologist to achieve optimal control of PD is an essential first step to alleviating anxiety,” they emphasized.

The researchers also advised addressing comorbidities, including cardiovascular disease, chronic pain, diabetes, gastrointestinal issues, hyperthyroidism, and lung disease, all of which can be associated with anxiety. Once comorbidities are addressed, they advised caution given the lack of evidence for efficacy of both pharmacologic and nonpharmacologic anxiety treatments for PD patients. However, first-tier treatment for anxiety could include monotherapy with serotonin-norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors, they said.

PD patients with depression and anxiety also may benefit from nonpharmacologic interventions, including exercise, mindfulness, relaxation therapy, and cognitive behavioral therapy the researchers said.

Although the algorithm may not differ significantly from current treatment protocols, it highlights aspects unique to PD patients, the researchers said. In particular, the algorithm shows “that interventions used for motor symptoms, for example, dopamine agonists, may be especially potent for mood in the PD population and that augmentation strategies, such as antipsychotics and lithium, may not be well tolerated given their outsized risk of adverse events in PD,” they said.

“While an article of this kind cannot hope to address the gap in knowledge on comparative efficacy between interventions, it can guide readers on the best strategies for implementation and risk mitigation in PD – essentially focusing more on effectiveness,” they concluded.

The study received no outside funding. Dr. Pontone disclosed serving as a consultant for Acadia Pharmaceuticals and Concert Pharmaceuticals.

Managing depression and anxiety in Parkinson’s disease should start with a review of medications and involve multidisciplinary care, according to a recent summary of evidence.

“Depression and anxiety have a complex relationship with the disease and while the exact mechanism for this association is unknown, both disturbances occur with increased prevalence across the disease course and when present earlier in life, increase the risk of PD by about twofold,” wrote Gregory M. Pontone, MD, of Johns Hopkins University, Baltimore, and colleagues.

Randomized trials to guide treatment of anxiety and depression in patients with Parkinson’s disease (PD) are limited, the researchers noted. However, data from a longitudinal study showed that PD patients whose depression remitted spontaneously or responded to treatment were able to attain a level of function similar to that of never-depressed PD patients, Dr. Pontone and colleagues said.

The researchers offered a pair of treatment algorithms to help guide clinicians in managing depression and anxiety in PD. However, a caveat to keep in mind is that “the benefit of antidepressant medications, used for depression or anxiety, can be confounded when motor symptoms are not optimally treated,” the researchers emphasized.

For depression, the researchers advised starting with some lab work; “at a minimum we suggest checking a complete blood count, metabolic panel, TSH, B12, and folate,” they noted. They recommended an antidepressant, cognitive-behavioral therapy, or both, as a first-line treatment, such as monotherapy with selective norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. They advised titrating the chosen monotherapy to a minimum effective dose over a 2- to 3-week period to assess response.

“We recommend continuing antidepressant therapy for at least 1 year based on literature in non-PD populations and anecdotal clinical experience. At 1 year, if not in remission, consider continuing treatment or augmenting to improve response,” the researchers said.

Based on the current DSM-5 criteria, up to one-third of PD patients have an unspecified anxiety disorder, the researchers said, and they recommended using anxiety rating scales to diagnose anxiety in PD. “Given the high prevalence of atypical anxiety syndromes in PD and their potential association with both motor and nonmotor symptoms of the disease, working with the neurologist to achieve optimal control of PD is an essential first step to alleviating anxiety,” they emphasized.

The researchers also advised addressing comorbidities, including cardiovascular disease, chronic pain, diabetes, gastrointestinal issues, hyperthyroidism, and lung disease, all of which can be associated with anxiety. Once comorbidities are addressed, they advised caution given the lack of evidence for efficacy of both pharmacologic and nonpharmacologic anxiety treatments for PD patients. However, first-tier treatment for anxiety could include monotherapy with serotonin-norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors, they said.

PD patients with depression and anxiety also may benefit from nonpharmacologic interventions, including exercise, mindfulness, relaxation therapy, and cognitive behavioral therapy the researchers said.

Although the algorithm may not differ significantly from current treatment protocols, it highlights aspects unique to PD patients, the researchers said. In particular, the algorithm shows “that interventions used for motor symptoms, for example, dopamine agonists, may be especially potent for mood in the PD population and that augmentation strategies, such as antipsychotics and lithium, may not be well tolerated given their outsized risk of adverse events in PD,” they said.

“While an article of this kind cannot hope to address the gap in knowledge on comparative efficacy between interventions, it can guide readers on the best strategies for implementation and risk mitigation in PD – essentially focusing more on effectiveness,” they concluded.

The study received no outside funding. Dr. Pontone disclosed serving as a consultant for Acadia Pharmaceuticals and Concert Pharmaceuticals.

Managing depression and anxiety in Parkinson’s disease should start with a review of medications and involve multidisciplinary care, according to a recent summary of evidence.

“Depression and anxiety have a complex relationship with the disease and while the exact mechanism for this association is unknown, both disturbances occur with increased prevalence across the disease course and when present earlier in life, increase the risk of PD by about twofold,” wrote Gregory M. Pontone, MD, of Johns Hopkins University, Baltimore, and colleagues.

Randomized trials to guide treatment of anxiety and depression in patients with Parkinson’s disease (PD) are limited, the researchers noted. However, data from a longitudinal study showed that PD patients whose depression remitted spontaneously or responded to treatment were able to attain a level of function similar to that of never-depressed PD patients, Dr. Pontone and colleagues said.

The researchers offered a pair of treatment algorithms to help guide clinicians in managing depression and anxiety in PD. However, a caveat to keep in mind is that “the benefit of antidepressant medications, used for depression or anxiety, can be confounded when motor symptoms are not optimally treated,” the researchers emphasized.

For depression, the researchers advised starting with some lab work; “at a minimum we suggest checking a complete blood count, metabolic panel, TSH, B12, and folate,” they noted. They recommended an antidepressant, cognitive-behavioral therapy, or both, as a first-line treatment, such as monotherapy with selective norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. They advised titrating the chosen monotherapy to a minimum effective dose over a 2- to 3-week period to assess response.

“We recommend continuing antidepressant therapy for at least 1 year based on literature in non-PD populations and anecdotal clinical experience. At 1 year, if not in remission, consider continuing treatment or augmenting to improve response,” the researchers said.

Based on the current DSM-5 criteria, up to one-third of PD patients have an unspecified anxiety disorder, the researchers said, and they recommended using anxiety rating scales to diagnose anxiety in PD. “Given the high prevalence of atypical anxiety syndromes in PD and their potential association with both motor and nonmotor symptoms of the disease, working with the neurologist to achieve optimal control of PD is an essential first step to alleviating anxiety,” they emphasized.

The researchers also advised addressing comorbidities, including cardiovascular disease, chronic pain, diabetes, gastrointestinal issues, hyperthyroidism, and lung disease, all of which can be associated with anxiety. Once comorbidities are addressed, they advised caution given the lack of evidence for efficacy of both pharmacologic and nonpharmacologic anxiety treatments for PD patients. However, first-tier treatment for anxiety could include monotherapy with serotonin-norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors, they said.

PD patients with depression and anxiety also may benefit from nonpharmacologic interventions, including exercise, mindfulness, relaxation therapy, and cognitive behavioral therapy the researchers said.

Although the algorithm may not differ significantly from current treatment protocols, it highlights aspects unique to PD patients, the researchers said. In particular, the algorithm shows “that interventions used for motor symptoms, for example, dopamine agonists, may be especially potent for mood in the PD population and that augmentation strategies, such as antipsychotics and lithium, may not be well tolerated given their outsized risk of adverse events in PD,” they said.

“While an article of this kind cannot hope to address the gap in knowledge on comparative efficacy between interventions, it can guide readers on the best strategies for implementation and risk mitigation in PD – essentially focusing more on effectiveness,” they concluded.

The study received no outside funding. Dr. Pontone disclosed serving as a consultant for Acadia Pharmaceuticals and Concert Pharmaceuticals.

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).

Patients with obesity who underwent bariatric surgery had 46% lower odds of stroke 1 year later, similar odds of stroke 3 years later, and 22% lower odds of stroke 5 years later, compared with matched control patients, in new research.

purestock/Thinkstock

Michael D. Williams, MD, presented the study findings (abstract A002) at the annual meeting of the American Society for Metabolic & Bariatric Surgery.

The findings are “very good news,” even though the protection against stroke declined further out from the surgery, John D. Scott, MD, scientific program chair of the ASMBS meeting, told this news organization.

The investigators matched more than 56,000 patients with obesity who had bariatric surgery with an equal number of similar patients who did not have this surgery, from a large national insurance database, in what they believe is the largest study of this to date.

“Any intervention that decreases your risk of [cardiovascular] events is good news,” said Dr. Scott, a clinical professor of surgery at the University of South Carolina, Greenville, and metabolic and bariatric surgery director at Prisma Health in Greenville, S.C. “And having a 22%-45% chance of reduction in stroke risk is a very worthwhile intervention.”

Asked how this would change the way clinicians inform patients of what to expect from bariatric surgery, he said: “I would advise patients that studies like this show that surgery would not increase your risk of having a stroke.

“This is consistent with many studies that show that the risks of all macrovascular events decrease after the comorbidity reductions seen after surgery.”

According to Dr. Scott, “the next steps might include a prospective randomized trial of medical treatment versus surgery alone for [cardiovascular]/stroke outcomes, but this is unlikely.”

Similarly, Dr. Williams told this news organization that “I would tell [patients] that surgery is an effective and durable method for weight loss. It also can improve comorbid conditions, particularly diabetes and hypertension.”

Even with this study, “I’m not sure it’s appropriate to say that bariatric surgery will reduce the risk of stroke,” he cautioned.

“However, as we continue to investigate the effects of bariatric surgery, this study contributes to the greater body of knowledge that suggests that reduction in ischemic stroke risk is yet another benefit of bariatric surgery.”

The assigned discussant, Corrigan L. McBride, MD, MBA wanted to know if the lower odds ratio at 1 year might be because preoperative patient selection might eliminate patients at high risk of poor cardiovascular outcomes.

Dr. Williams, a resident at Rush Medical College, Chicago, replied that it is difficult to eliminate potential selection bias, despite best efforts, but this study shows that he can tell patients: “Having surgery is not going to increases your risk of stroke.”

“This is an important study,” Dr. McBride, professor and chief of minimally invasive surgery and bariatric surgery, University of Nebraska Medical Center, Omaha, told this news organization.

“It is the first large study to show a decreased [or no increased] risk of stroke 1, 3, and 5 years after bariatric surgery compared to matched patients, and it had enough data to look at stroke as a standalone endpoint,” Dr. McBride said. “It is important too, for patients and their physicians to understand that there is a lower chance of them having a stroke if they have surgery than if they do not.”
 

‘Important,’ ‘good news’ for stroke risk after bariatric surgery

The impact of bariatric surgery on remission of type 2 diabetes is well known, Dr. Williams noted, and other studies have reported how bariatric surgery affects the risk of major adverse cardiovascular events – a composite of stroke, myocardial infarction, coronary artery disease, and all-cause death – including a study presented in the same meeting session.

However, a very large sample size is needed to be able to demonstrate the effect of bariatric surgery on stroke, since stroke is a rare event.

The researchers analyzed data from the Mariner (PearlDiver.) all-payer insurance national claims database of patients in the United States.

They matched 56,514 patients with a body mass index over 35 kg/m² and comorbidities or a BMI of more than 40 who underwent sleeve gastrectomy or Roux-en-Y gastric bypass during 2010-2019 with 56,514 control patients who did not undergo bariatric surgery.

A year after bariatric surgery, patients in that group had a lower stroke rate than patients in the control group (0.6% vs. 1.2%), and they had close to 50% lower odds of having a stroke (odds ratio, 0.54; 95% CI, 0.47-0.61).

Three years after bariatric surgery, there were 44,948 patients in each group; the rate of stroke was 2.1% in the surgery group and 2.2% in the control group, and there was no significant difference in the odds of having a stroke (OR, 0.96; 95% CI, 0.91-1.00).

Five years after bariatric surgery, there were 27,619 patients in each group; the stroke rate was lower in the bariatric surgery group than in the control group (2.8% vs 3.6%), but reduced odds of stroke was not as great as after 1 year (OR, 0.78; 95% CI, 0.65-0.90).

Dr. Williams has no relevant financial disclosures. Dr. McBride and Dr. Scott disclosed that they are speakers/trainers/faculty advisers for Gore. Dr. Scott is also a consultant for C-SATS (part of Johnson & Johnson).