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Treating sleep apnea lowers MI and stroke risk
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.
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.
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.
FROM SLEEP 2021
Memory benefit seen with antihypertensives crossing blood-brain barrier
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.
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.
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.
FROM HYPERTENSION
Stopping Empagliflozin Unmasks Heart Failure
SGLT2 inhibitors have been shown to have a role in the management of heart failure in patients with type 2 diabetes mellitus, but there is a risk of exacerbation when discontinued.
About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).1 Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.2 We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF.
Case Presentation
A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.
The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A1c level from 1 month prior to the presentation was 6.4%.
Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.
Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.
Discussion
T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.5
SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.8
The EMPRISE study specifically examined empagliflozin and its effects on hospitalization for HF.2 When compared with patients treated with sitagliptin, there was a statistically significant decrease in hospitalization for HF in patients with T2DM, both with and without preexisting cardiovascular disease.
This case highlights the relationship between T2DM and HF. We also show how the use of empagliflozin may have helped manage the patient’s undiagnosed HF and how its discontinuation luckily unmasked it. Routine evaluation for HF in patients with T2DM is not done, but likely there are patients who would benefit, especially given the strong, albeit less known, association between these 2 conditions.
Further studies are needed to determine the type of patients who would benefit most from HF screening. For now, the best practice is to obtain a complete medical history that includes current and recently discontinued medications as well a thorough physical examination for signs of fluid overload and cardiovascular compromise. Patients who may have signs concerning for HF can have appropriate testing and intervention.
Conclusions
SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.
1. Thomas MC. Type 2 diabetes and heart failure: challenges and solutions. Curr Cardiol Rev. 2016;12(3):249-255. doi:10.2174/1573403X12666160606120254
2. Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the EMPRISE study. Circulation. 2019;139(25):2822-2830. doi:10.1161/CIRCULATIONAHA.118.039177
3. Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care. 2018;41(1):11-13. doi:10.2337/dci17-0052
4. Thrainsdottir I, Aspelund T, Thorheirsson G, et al. The association between glucose abnormalities and heart failure in the population-based Reykjavík study. Diabetes Care. 2005;28(3):612-616. doi:10.2337/diacare.28.3.612
5. Bell D, Goncalves E. Heart failure in the patient with diabetes: epidemiology, aetiology, prognosis, therapy and the effect of glucose-lowering medications. Diabetes Obes Metab. 2019;21(6):1277-1290. doi:10.1111/dom.13652
6. Nair S, Wilding JPH. Sodium glucose cotransporter 2 Inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34-42. doi:10.1210/jc.2009-0473
7. Ali A, Bain S, Hicks D, et al; Improving Diabetes Steering Committee. SGLT2 inhibitors: cardiovascular benefits beyond HbA1c- translating evidence into practice. Diabetes Ther. 2019;10(5):1595-1622. doi:10.1007/s13300-019-0657-8
8. Zinman B, Wanner C, Lachin J, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
SGLT2 inhibitors have been shown to have a role in the management of heart failure in patients with type 2 diabetes mellitus, but there is a risk of exacerbation when discontinued.
SGLT2 inhibitors have been shown to have a role in the management of heart failure in patients with type 2 diabetes mellitus, but there is a risk of exacerbation when discontinued.
About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).1 Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.2 We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF.
Case Presentation
A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.
The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A1c level from 1 month prior to the presentation was 6.4%.
Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.
Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.
Discussion
T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.5
SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.8
The EMPRISE study specifically examined empagliflozin and its effects on hospitalization for HF.2 When compared with patients treated with sitagliptin, there was a statistically significant decrease in hospitalization for HF in patients with T2DM, both with and without preexisting cardiovascular disease.
This case highlights the relationship between T2DM and HF. We also show how the use of empagliflozin may have helped manage the patient’s undiagnosed HF and how its discontinuation luckily unmasked it. Routine evaluation for HF in patients with T2DM is not done, but likely there are patients who would benefit, especially given the strong, albeit less known, association between these 2 conditions.
Further studies are needed to determine the type of patients who would benefit most from HF screening. For now, the best practice is to obtain a complete medical history that includes current and recently discontinued medications as well a thorough physical examination for signs of fluid overload and cardiovascular compromise. Patients who may have signs concerning for HF can have appropriate testing and intervention.
Conclusions
SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.
About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).1 Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.2 We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF.
Case Presentation
A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.
The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A1c level from 1 month prior to the presentation was 6.4%.
Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.
Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.
Discussion
T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.5
SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.8
The EMPRISE study specifically examined empagliflozin and its effects on hospitalization for HF.2 When compared with patients treated with sitagliptin, there was a statistically significant decrease in hospitalization for HF in patients with T2DM, both with and without preexisting cardiovascular disease.
This case highlights the relationship between T2DM and HF. We also show how the use of empagliflozin may have helped manage the patient’s undiagnosed HF and how its discontinuation luckily unmasked it. Routine evaluation for HF in patients with T2DM is not done, but likely there are patients who would benefit, especially given the strong, albeit less known, association between these 2 conditions.
Further studies are needed to determine the type of patients who would benefit most from HF screening. For now, the best practice is to obtain a complete medical history that includes current and recently discontinued medications as well a thorough physical examination for signs of fluid overload and cardiovascular compromise. Patients who may have signs concerning for HF can have appropriate testing and intervention.
Conclusions
SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.
1. Thomas MC. Type 2 diabetes and heart failure: challenges and solutions. Curr Cardiol Rev. 2016;12(3):249-255. doi:10.2174/1573403X12666160606120254
2. Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the EMPRISE study. Circulation. 2019;139(25):2822-2830. doi:10.1161/CIRCULATIONAHA.118.039177
3. Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care. 2018;41(1):11-13. doi:10.2337/dci17-0052
4. Thrainsdottir I, Aspelund T, Thorheirsson G, et al. The association between glucose abnormalities and heart failure in the population-based Reykjavík study. Diabetes Care. 2005;28(3):612-616. doi:10.2337/diacare.28.3.612
5. Bell D, Goncalves E. Heart failure in the patient with diabetes: epidemiology, aetiology, prognosis, therapy and the effect of glucose-lowering medications. Diabetes Obes Metab. 2019;21(6):1277-1290. doi:10.1111/dom.13652
6. Nair S, Wilding JPH. Sodium glucose cotransporter 2 Inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34-42. doi:10.1210/jc.2009-0473
7. Ali A, Bain S, Hicks D, et al; Improving Diabetes Steering Committee. SGLT2 inhibitors: cardiovascular benefits beyond HbA1c- translating evidence into practice. Diabetes Ther. 2019;10(5):1595-1622. doi:10.1007/s13300-019-0657-8
8. Zinman B, Wanner C, Lachin J, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
1. Thomas MC. Type 2 diabetes and heart failure: challenges and solutions. Curr Cardiol Rev. 2016;12(3):249-255. doi:10.2174/1573403X12666160606120254
2. Patorno E, Pawar A, Franklin J, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care: a first analysis from the EMPRISE study. Circulation. 2019;139(25):2822-2830. doi:10.1161/CIRCULATIONAHA.118.039177
3. Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care. 2018;41(1):11-13. doi:10.2337/dci17-0052
4. Thrainsdottir I, Aspelund T, Thorheirsson G, et al. The association between glucose abnormalities and heart failure in the population-based Reykjavík study. Diabetes Care. 2005;28(3):612-616. doi:10.2337/diacare.28.3.612
5. Bell D, Goncalves E. Heart failure in the patient with diabetes: epidemiology, aetiology, prognosis, therapy and the effect of glucose-lowering medications. Diabetes Obes Metab. 2019;21(6):1277-1290. doi:10.1111/dom.13652
6. Nair S, Wilding JPH. Sodium glucose cotransporter 2 Inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34-42. doi:10.1210/jc.2009-0473
7. Ali A, Bain S, Hicks D, et al; Improving Diabetes Steering Committee. SGLT2 inhibitors: cardiovascular benefits beyond HbA1c- translating evidence into practice. Diabetes Ther. 2019;10(5):1595-1622. doi:10.1007/s13300-019-0657-8
8. Zinman B, Wanner C, Lachin J, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
Bariatric surgery tied to 22% lower 5-year stroke risk
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.
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.
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.
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).
FROM ASMBS 2021
Prophylactic anticoagulation tied to lower death rate in COVID
Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.
In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.
And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.
The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.
“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.
“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.
Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.
“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”
They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”
Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.
The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.
“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.
“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”
Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.
Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.
The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.
Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.
In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.
Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).
Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.
However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
Study boosts confidence
Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.
“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.
“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.
The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.
In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.
And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.
The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.
“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.
“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.
Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.
“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”
They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”
Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.
The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.
“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.
“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”
Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.
Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.
The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.
Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.
In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.
Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).
Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.
However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
Study boosts confidence
Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.
“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.
“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.
The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Prophylactic anticoagulation to prevent venous thromboembolism (VTE) was associated with reduced 60-day mortality in patients with COVID-19 who were ill enough to require hospitalization, a new report shows.
In a cohort study of more than 1,300 hospitalized patients with COVID-19 infection across 30 hospitals in Michigan, both prophylactic- and therapeutic-dose anticoagulation were associated with reduced in-hospital mortality; however, at 60 days, only prophylactic-dose anticoagulation remained associated with lower mortality.
And adherence was key; nonadherence, or missing 2 days or more of anticoagulation, was linked to more deaths at 60 days.
The findings, which were published online June 11 in JAMA Network Open, are final proof that a prophylactic anticoagulation strategy for the hospitalized COVID population is, indeed, the right one, Valerie M. Vaughn, MD, director of hospital medicine research at the University of Utah, Salt Lake City, said in an interview.
“We’ve probably always known that patients with COVID need prophylaxis for VTE, but we found that early on, unfortunately, that wasn’t being done,” Dr. Vaughn said.
“Now, we see that prophylactic rates have increased. We always knew to use anticoagulation prophylactically in patients who were hospitalized with infection because of their risk for VTE, so this study just drives home that proper adherence to an anticoagulation protocol improves mortality,” she said.
Dr. Vaughn was on the front lines when COVID-19 came to Michigan, where the research was conducted.
“We probably should have been anticoagulating from the get-go, but you have to remember that in the early days of COVID, the hospitals in Michigan were being overwhelmed. They didn’t have PPE. They were taking care of patients outside of their typical hospital beds or setting up field hospitals,” she said. “It was not quite as bad as New York, but at the University of Michigan, we set up four or five ICUs outside of our normal care.”
They also converted the top floor of their pediatric hospital into an ICU to take care of patients with COVID during the first surge, she added. “We didn’t know much about this disease, but faced with this influx of patients, many of whom were dying with blood clots, we had to do something.”
Some hospitals began prophylactically anticoagulating their patients, but others hesitated before adopting the strategy. “But now we feel confident that prophylactic anticoagulation, done according to the right protocol, with no interruptions in the treatment, is beneficial,” Dr. Vaughn said.
The best medication choice is enoxaparin (Lovenox), which can be given once a day, as opposed to heparin, which needs to be given via injection three times a day, she said.
“Prophylactic dose anticoagulation is typically given by an injection under the skin, but a lot of times, I’ve had patients tell me they feel like a human pin cushion and have all these bruises from being stuck with needles every day, which I can totally relate to,” she said.
“It is important for us as clinicians to explain that we’re having to poke our patients because it is good for them and will help them fight COVID,” she added. “Also having the once-a-day option is going to be a lot better for adherence, and adherence to the protocol, not missing any days, is key to the better outcome.”
Dr. Vaughn and her team reviewed the charts of 1,351 patients (48% women, 49% Black, median age 64 [range 52-75]) who were hospitalized throughout Michigan during the first several months of the COVID-19 pandemic, from March to June 2020.
Only 18 patients (1.3%) had a confirmed VTE and 219 patients (16.2%) received treatment-dose anticoagulation.
The researchers noted that use of treatment-dose anticoagulation without imaging ranged from 0% to 29% across hospitals and increased significantly over time.
Of the 1,127 patients who received anticoagulation, 392 (34.8%) missed 2 days or more of prophylaxis.
In addition, there were varying rates of missed prophylaxis among the hospitals, from 11% to 61%, but these rates decreased markedly over time.
Missed doses were associated with a higher 60-day mortality (adjusted hazard ratio, 1.31; 95% confidence interval, 1.03-1.67), but not in-hospital mortality (aHR, 0.97; 95% CI, 0.91-1.03).
Compared with no anticoagulation, receiving any dose of anticoagulation was associated with lower in-hospital mortality.
However, only prophylactic-dose anticoagulation remained associated with lower mortality at 60 days. The adjusted hazard ratio for prophylactic-dose anticoagulation was 0.71 (95% CI, 0.51-0.90), compared with 0.92 (95% CI, 0.63-1.35) for treatment-dose anticoagulation.
Study boosts confidence
Despite its limitations, the study should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with COVID-19, write Andrew B. Dicks, MD, and Ido Weinberg, MD, from Massachusetts General Hospital, Boston, in an invited commentary.
“Practically, we still lack the granular data we need to help guide us in patient-by-patient decision-making – such as anticoagulation agent choice, dosage, and duration of therapy – especially as dictated by acuity of patient illness,” Dr. Dicks and Dr. Weinberg note.
“While we still await the data from randomized controlled trials to guide the optimal anticoagulation dose and duration, this study adds significant merit to the previously published recommendations from several different medical organizations regarding the use of prophylactic anticoagulation in hospitalized patients with COVID-19,” Dr. Dicks told this news organization.
The study was supported by Blue Cross and Blue Shield of Michigan and Blue Care Network as part of their Value Partnerships program. Dr. Vaughn has reported receiving speaking fees from Thermo Fisher Scientific. Dr. Dicks and Dr. Weinberg have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
U.S., international MIS-C studies yield disparate results
That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.
In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.
The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.
The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).
Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).
In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).
Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.
Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”
Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.
Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
Maybe not so standard
Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.
The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.
In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.
Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).
After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.
Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.
Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.
BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.
Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.
Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.
“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”
For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”
The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.
In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.
The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.
The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).
Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).
In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).
Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.
Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”
Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.
Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
Maybe not so standard
Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.
The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.
In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.
Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).
After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.
Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.
Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.
BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.
Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.
Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.
“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”
For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”
The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
That requires rapid pragmatic evaluation of therapies. Two real-world observational studies published online June 16 in The New England Journal of Medicine do that, with differing results.
In the Overcoming COVID-19 study, investigators assessed initial therapy and outcomes for patients with MIS-C using surveillance data from 58 pediatric hospitals nationwide.
The results suggest that patients with MIS-C who were younger than 21 years of age and who were initially treated with intravenous immunoglobulin (IVIG) plus glucocorticoids fared better in terms of cardiovascular function.
The study included 518 children (median age, 8.7 years) who were admitted to the hospital between March and October 2020 and who received at least one immunomodulatory therapy. In a propensity score–matched analysis, those given IVIG plus glucocorticoids (n = 103) had a lower risk for the primary outcome of cardiovascular dysfunction on or after day 2 than those given IVIG alone (n = 103), at 17% versus 31% (risk ratio, 0.56; 95% confidence interval, 0.34-0.94).
Risks for individual aspects of the study’s composite outcome were also lower with IVIG plus glucocorticoids. Left ventricular dysfunction occurred in 8% and 17%, respectively (RR, 0.46; 95% CI, 0.19-1.15). Shock requiring vasopressor use emerged in 13% and 24%, respectively (RR, 0.54; 95% CI, 0.29-1.00).
In addition, there were fewer cases in which adjunctive therapy was given on day one among those who received combination therapy than among those who received IVIG alone, at 34% versus 70% (RR, 0.49; 95% CI, 0.36-0.65), but the risk for fever was not lower on or after day two (31% and 40%, respectively; RR, 0.78; 95% CI, 0.53-1.13).
Lead author Mary Beth F. Son, MD, director of the rheumatology program at Boston Children’s Hospital, who is also associate professor of pediatrics at Harvard Medical School, stressed that the study did not assess which MIS-C patients should receive treatment. “Rather, we studied children who had been treated with one of two initial regimens and then assessed short-term outcomes,” she told this news organization.
Going forward, it will be important to study which children should receive immunomodulatory treatment, Dr. Son said. “Specifically, can the less ill children receive IVIG alone or no treatment? This is an unanswered question at the moment, which could be addressed with a randomized controlled trial.”
Future directions, she added, will include assessing long-term cardiac outcomes for patients with MIS-C as well as studying outpatient regimens, especially those that involve steroids.
Earlier this year, French investigators found better outcomes with combined corticosteroids and IVIG than with IVIG alone. They suggested that combination therapy should be the standard of care, given the present state of therapeutic knowledge.
Maybe not so standard
Different results emerged, however, from an international study of MIS-C that compared three, rather than two, treatment approaches. Collaborators from the Best Available Treatment Study for MIS-C (BATS) evaluated data for 614 children with suspected MIS-C between June 2020 and February 2021 in 32 countries and found no substantial differences in recovery among children whose primary treatment was IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone.
The study by Andrew J. McArdle, MB BChir, MSC, a clinical research fellow at Imperial College London, and colleagues was published June 16 in The New England Journal of Medicine.
In the BATS cohort, 246 received IVIG alone, 208 received IVIG plus glucocorticoids, and 99 received glucocorticoids alone. Twenty-two patients received other combinations, including biologics, and 39 received no immunomodulatory therapy.
Among patients who were included in the primary analysis, death occurred or inotropic or ventilatory support was employed in 56 of 180 of the patients who received IVIG plus glucocorticoids, compared with 44 of 211 patients treated with IVIG alone, for an adjusted odds ratio (aOR) of 0.77 (95% CI, 0.33-1.82). Among those who received glucocorticoids alone, 17 of 83 met the primary endpoint of death or inotropic or ventilatory support, for an aOR relative to IVIG alone of 0.54 (95% CI, 0.22-1.33).
After adjustments, the likelihood for reduced disease severity was similar in the two groups relative to IVIG alone, at 0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone. Time to reduction in disease severity was also comparable across all groups.
Some of the differences between the U.S. study and the global studies could be the result of the larger size of the international cohort and possibly a difference in the strains of virus in the United States and abroad, according to S. Sexson Tejtel, MD, PhD, MPH, a pediatric cardiologist at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, Houston, Texas. “Some strains make children sicker than others, and they’re going to need more treatment,” said Dr. Sexson Tejtel, who was not involved in either study.
Dr. Sexson Tejtel also noted that the U.S. researchers did not assess outcomes among children treated with steroids alone. “It would be interesting to know what steroids alone look like in the U.S. MIS-C population,” she said in an interview.
BATS corresponding author Michael Levin, MBE, PhD, FRCPCH, an Imperial College professor of pediatrics and international child health, told this news organization that the differing results may have arisen because of the international study’s three-treatment focus, its wider spectrum of patients, and its different endpoints: Death and inotropic support on or after day 2, versus echocardiographic left ventricular dysfunction or inotropic usage.
Regardless of the differences between the two studies, neither establishes the most effective single or combination treatment, writes Roberta L. DeBiasi, MD, of the Division of Pediatric Infectious Diseases at Children’s National Hospital and Research Institute and George Washington University, Washington, in an accompanying editorial. “Specifically, neither study was powered to include an evaluation of approaches that steer away from broad immunosuppression with glucocorticoids and that focus on more targeted and titratable treatments with biologic agents, such as anakinra and infliximab,” she writes.
Dr. DeBiasi adds that long-term follow-up studies of cardiac and noncardiac outcomes in these patients will launch soon. “Meanwhile, continued collaboration across centers is essential to decreasing the short-term incidence of death and complications,” she writes.
“It will be interesting as we apply results from these studies as they come out to see how they change our practice,” Dr. Sexson Tejtel said. “And it would be good to have some randomized clinical trials.”
For Dr. Levin, the bottom line is that all three treatments are associated with recovery for a majority of children. “This is good news for clinicians who have been guessing which treatment to use,” he said. “Both studies are attempts to provide doctors with some evidence on which to base treatment decisions and are not the final answer. Our study is ongoing, and with larger numbers of patients it may give clearer answers.”
The Overcoming COVID-19 study was funded by the U.S. Centers for Disease Control and Prevention. Several coauthors have reported support from industry outside of the submitted work. BATS was funded by the European Union’s Horizons 2020 Program. The study authors have disclosed no relevant financial relationships. One coauthor’s spouse is employed by GlaxoSmithKline. Dr. DeBiasi and Dr. Sexson Tejtel have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Reversal agents curb DOAC-related bleeding but deaths still high
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
Agents that reverse the effect of direct oral anticoagulants (DOACs) are highly effective in patients with severe bleeding, but mortality rates remain high despite their use, a meta-analysis shows.
Effective hemostasis was achieved in 78.5% of patients treated with a reversal agent, whereas failure to achieve hemostasis was associated with more than a threefold higher relative risk for death (relative risk, 3.63; 95% confidence interval, 2.56-5.16).
“This has implications in practice because it emphasizes the need for achieving effective hemostasis, if not with only one agent, trying other agents or treatment modalities, because it is a strong predictor of survival,” lead author Antonio Gómez-Outes, MD, PhD, said in an interview.
The bad news, he said, is that the mortality rate was still significant, at 17.7%, and approximately half of patients with DOAC-related severe intracranial bleeding survived with long-term moderate/severe disability.
“The lesson is to prevent these bleeding events because once they appear, even if you give an antidote, the outcome is poor, particularly for intracranial bleeding,” said Dr. Gómez-Outes, division of pharmacology and clinical drug evaluation, Spanish Agency for Medicines and Medical Devices, Madrid.
To put this in context, mortality rates were close to 50% after intracranial bleeding a decade ago when there were no antidotes or reversal agents, he observed. “So to some extent, patient care has improved, and the outcome has improved, but there is a long road to improve regarding disability.”
More than 100,000 DOAC-related major bleeding cases occur each year in the United States and European Union, Dr. Gómez-Outes said, and about half are severe enough to require hospitalization and potentially the use of a reversal agent. These include idarucizumab (Praxbind) for dabigatran reversal and prothombin complex concentrates (4CCC) or andexanet alpha (Andexxa) for reversal of direct factor Xa inhibitors like rivaroxaban, apixaban, and edoxaban.
As reported in the June 22 issue of the Journal of the American College of Cardiology, the meta-analysis comprised 4,735 patients (mean age, 77 years; 57% male) with severe DOAC-related bleeding who received 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) in 60 studies between January 2010 and December 2020.
Atrial fibrillation (AFib) was the most common reason for use of a DOAC (82%), followed by venous thromboembolism (14%). Rivaroxaban was used in 36%, apixaban in 32%, dabigatran in 31%, and edoxaban in 1%.
The index bleeding event was intracranial hemorrhage (ICH) in 55%. Anticoagulation was restarted in 57% of patients an average of 11 days after admission.
Mortality rates were 20.2% in patients with ICH and 15.4% in those with extracranial bleeding. There were no differences in death rates by reversal agent used, type of study, risk for bias, or study sponsorship in meta-regression analysis.
Rebleeding occurred in 13.2% of patients; 82.0% of these events were described as an ICH, and 78.0% occurred after anticoagulation was restarted.
The overall rate of thromboembolism was 4.6%. The risk was particularly high with andexanet, at 10.7%, and relatively low with idarucizumab (3.8%) and 4PCC (4.3%), the authors note.
“Our meta-analysis suggests specific reversal with andexanet is not superior to unspecific reversal with 4PCC, and that’s good news because many centers, in many countries, have no access to specific antidotes that are more costly,” Dr. Gómez-Outes said. “4PCC is an effective and relatively safe drug, so it’s still a good option for these patients.”
Labeling for andexanet includes a warning for thromboembolic events, but in the absence of direct comparisons, the findings should be interpreted with caution, he added. Further insights are expected from an ongoing randomized trial of andexanet and standard of care in 900 patients who present with acute ICH less than 15 hours after taking an oral factor Xa inhibitor. The preliminary completion date is set for 2023.
“The meta-analysis raises awareness about the rates of mortality and thromboembolism after reversal agent administration, although understanding the implications of these data is challenging,” Christopher Granger, MD, and Sean P. Pokomey, MD, MBA, Duke University Medical Center, Durham, N.C., say in an accompanying editorial.
The fact that failure to achieve hemostasis was associated with death is expected and might be related to the way hemostasis was defined, rather than the actual failure of the hemostatic treatments, they suggest. “The prothrombotic effects of each agent, including andexanet, need to be better understood, as clinicians work toward including reversal agents into algorithms for bleeding management.”
Effective hemostasis was defined in the studies through various methods as: “Excellent/good” using the Sarode and ANNEXA-4 scales; “yes” in the International Society on Thrombosis and Hemostasis Scale; and with other scales and through clinical judgment.
Although the size of the meta-analysis dwarfs previous reviews, the editorialists and authors point out that 47 of the 60 studies were retrospective, only two had control groups, and 45 had a high risk for bias.
In general, there was also poor reporting of key clinical data, such as postbleeding anticoagulation management, and a limitation of the mortality analysis is that it was based in selected patients with effective hemostasis assessed within 48 hours, which may not capture early deaths, the authors note.
“The morbidity and mortality from ischemic strokes as a result of undertreatment of stroke prevention in patients with AFib continue to dwarf the bleeding related mortality among patients with AFib and on DOACs, and thus the number one priority is to treat nearly all patients with AFib with a DOAC,” Dr. Granger and Dr. Pokomey conclude. “The availability of reversal agents for DOACs should provide reassurance, with another tool in our armamentarium, to providers to prescribe OACs for stroke prevention.”
No funding/grant support was received to conduct the study. Coauthor Ramón Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors report no relevant financial relationships. Dr. Granger has received research and consulting fees from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Bayer, Janssen, Boston Scientific, Apple, AstraZeneca, Novartis, AbbVie, Biomed, CeleCor, GSK, Novartis, Medtronic, Merck, Novo Nordisk, Philips, Rho, and the U.S. Food and Drug Administration. Dr. Pokomey has received modest consulting support from Bristol Myers Squibb, Pfizer, Boston Scientific, Medtronic, Janssen, and Zoll; modest research support from Gilead, Boston Scientific, Bristol Myers Squibb, Pfizer, and Janssen; and significant research support from the FDA.
A version of this article first appeared on Medscape.com.
AHA: Don’t delay COVID shot while CDC reviews myocarditis cases
While the investigation into cases of myocarditis possibly associated with COVID vaccines proceeds, the American Heart Association/American Stroke Association (ASA) continue to urge everyone who is eligible for the vaccine to get it without delay.
“We remain confident that the benefits of vaccination far exceed the very unusual risks,” the leadership of the AHA/ASA said in a statement issued June 12.
“The risks of COVID-19 infection include its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including lingering consequences affecting the heart, brain, vascular system, and other organs after infection,” they point out.
Late last week, the Centers for Disease Control and Prevention alerted health care providers that the COVID-19 Vaccine Safety Technical Work Group (VaST) of the Advisory Committee on Immunization Practices (ACIP) will meet June 18 to review cases of myocarditis reported in adolescents and young adults after they received a COVID-19 vaccine manufactured by Pfizer-BioNTech or Moderna.
The CDC is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.
These cases may occur more often in males than females and more frequently after the second dose than the first dose of either mRNA vaccine. Symptoms typically occur in the 3 days after administration.
“The CDC’s ongoing investigation into cases of suspected myocarditis reflects a strong and steadfast commitment to transparency and the importance of scientific rigor on all fronts. We applaud the CDC’s unwavering efforts to lead our nation’s scientific and public health efforts, including ensuring the continued safety of the COVID-19 vaccines,” the AHA/ASA states.
They emphasize that vaccinations should continue, and say it’s important to consider the details of the suspected myocarditis cases being investigated by the CDC.
As of June 11, more than 306 million doses of COVID-19 vaccines have been administered in the United States (since Dec. 14, 2020) and nearly 43% of Americans – more than 142 million people – are now fully vaccinated.
According to the June 10 CDC VAERS report detailing adverse events through May 31:
- 789 cases of suspected myocarditis have been reported, with 475 involving people younger than 30 years; 79 cases reported were in patients 16 or 17 years old.
- The vast majority (81%) of the 270 patients younger than 30 years who were discharged from care after suspected myocarditis related to COVID-19 vaccination have recovered fully; the remaining 19% of patients report ongoing symptoms or complete data are missing.
- 196 cases of suspected myocarditis after a COVID-19 vaccine were reported in young adults 18 to 24 years of age, which is higher than expected for this age group.
As of May 31, only about 9% of the COVID-19 vaccine doses administered were to people 16 to 24 years of age, which is why this “higher-than-normal rate of possible myocarditis cases” warrants investigation, the AHA/ASA says.
They note that these suspected myocarditis cases were reported to VAERS because of their proximity to COVID-19 vaccine administration.
It remains to be determined which cases meet the clinical criteria for a diagnosis of myocarditis and whether they have any direct connection to the COVID-19 vaccine, the AHA/ASA says.
They urge all health care professionals to be aware of “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation.
They advise asking patients who present with symptoms related to these conditions about the timing of recent COVID vaccinations, as needed, to confirm the diagnosis and provide appropriate treatment quickly.
The AHA will be at the CDC’s June 18 meeting to review the latest evidence on cases of suspected myocarditis after the COVID-19 vaccine, the statement adds.
The statement notes that it reflects the views of the AHA/ASA and its scientific leadership, including current president Mitchel S.V. Elkind, MD, PhD; immediate past-president Robert A. Harrington, MD; president-elect Donald M. Lloyd-Jones, MD; AHA/ASA chief science and medical officer Mariell Jessup, MD; and chief medical officer for prevention Eduardo Sanchez, MD, MPH.
A version of this article first appeared on Medscape.com.
While the investigation into cases of myocarditis possibly associated with COVID vaccines proceeds, the American Heart Association/American Stroke Association (ASA) continue to urge everyone who is eligible for the vaccine to get it without delay.
“We remain confident that the benefits of vaccination far exceed the very unusual risks,” the leadership of the AHA/ASA said in a statement issued June 12.
“The risks of COVID-19 infection include its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including lingering consequences affecting the heart, brain, vascular system, and other organs after infection,” they point out.
Late last week, the Centers for Disease Control and Prevention alerted health care providers that the COVID-19 Vaccine Safety Technical Work Group (VaST) of the Advisory Committee on Immunization Practices (ACIP) will meet June 18 to review cases of myocarditis reported in adolescents and young adults after they received a COVID-19 vaccine manufactured by Pfizer-BioNTech or Moderna.
The CDC is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.
These cases may occur more often in males than females and more frequently after the second dose than the first dose of either mRNA vaccine. Symptoms typically occur in the 3 days after administration.
“The CDC’s ongoing investigation into cases of suspected myocarditis reflects a strong and steadfast commitment to transparency and the importance of scientific rigor on all fronts. We applaud the CDC’s unwavering efforts to lead our nation’s scientific and public health efforts, including ensuring the continued safety of the COVID-19 vaccines,” the AHA/ASA states.
They emphasize that vaccinations should continue, and say it’s important to consider the details of the suspected myocarditis cases being investigated by the CDC.
As of June 11, more than 306 million doses of COVID-19 vaccines have been administered in the United States (since Dec. 14, 2020) and nearly 43% of Americans – more than 142 million people – are now fully vaccinated.
According to the June 10 CDC VAERS report detailing adverse events through May 31:
- 789 cases of suspected myocarditis have been reported, with 475 involving people younger than 30 years; 79 cases reported were in patients 16 or 17 years old.
- The vast majority (81%) of the 270 patients younger than 30 years who were discharged from care after suspected myocarditis related to COVID-19 vaccination have recovered fully; the remaining 19% of patients report ongoing symptoms or complete data are missing.
- 196 cases of suspected myocarditis after a COVID-19 vaccine were reported in young adults 18 to 24 years of age, which is higher than expected for this age group.
As of May 31, only about 9% of the COVID-19 vaccine doses administered were to people 16 to 24 years of age, which is why this “higher-than-normal rate of possible myocarditis cases” warrants investigation, the AHA/ASA says.
They note that these suspected myocarditis cases were reported to VAERS because of their proximity to COVID-19 vaccine administration.
It remains to be determined which cases meet the clinical criteria for a diagnosis of myocarditis and whether they have any direct connection to the COVID-19 vaccine, the AHA/ASA says.
They urge all health care professionals to be aware of “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation.
They advise asking patients who present with symptoms related to these conditions about the timing of recent COVID vaccinations, as needed, to confirm the diagnosis and provide appropriate treatment quickly.
The AHA will be at the CDC’s June 18 meeting to review the latest evidence on cases of suspected myocarditis after the COVID-19 vaccine, the statement adds.
The statement notes that it reflects the views of the AHA/ASA and its scientific leadership, including current president Mitchel S.V. Elkind, MD, PhD; immediate past-president Robert A. Harrington, MD; president-elect Donald M. Lloyd-Jones, MD; AHA/ASA chief science and medical officer Mariell Jessup, MD; and chief medical officer for prevention Eduardo Sanchez, MD, MPH.
A version of this article first appeared on Medscape.com.
While the investigation into cases of myocarditis possibly associated with COVID vaccines proceeds, the American Heart Association/American Stroke Association (ASA) continue to urge everyone who is eligible for the vaccine to get it without delay.
“We remain confident that the benefits of vaccination far exceed the very unusual risks,” the leadership of the AHA/ASA said in a statement issued June 12.
“The risks of COVID-19 infection include its potentially fatal consequences and the potential long-term health effects that are still revealing themselves, including lingering consequences affecting the heart, brain, vascular system, and other organs after infection,” they point out.
Late last week, the Centers for Disease Control and Prevention alerted health care providers that the COVID-19 Vaccine Safety Technical Work Group (VaST) of the Advisory Committee on Immunization Practices (ACIP) will meet June 18 to review cases of myocarditis reported in adolescents and young adults after they received a COVID-19 vaccine manufactured by Pfizer-BioNTech or Moderna.
The CDC is monitoring the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) for cases of myocarditis that have been associated with the mRNA vaccines against SARS-CoV-2 from Pfizer and Moderna.
These cases may occur more often in males than females and more frequently after the second dose than the first dose of either mRNA vaccine. Symptoms typically occur in the 3 days after administration.
“The CDC’s ongoing investigation into cases of suspected myocarditis reflects a strong and steadfast commitment to transparency and the importance of scientific rigor on all fronts. We applaud the CDC’s unwavering efforts to lead our nation’s scientific and public health efforts, including ensuring the continued safety of the COVID-19 vaccines,” the AHA/ASA states.
They emphasize that vaccinations should continue, and say it’s important to consider the details of the suspected myocarditis cases being investigated by the CDC.
As of June 11, more than 306 million doses of COVID-19 vaccines have been administered in the United States (since Dec. 14, 2020) and nearly 43% of Americans – more than 142 million people – are now fully vaccinated.
According to the June 10 CDC VAERS report detailing adverse events through May 31:
- 789 cases of suspected myocarditis have been reported, with 475 involving people younger than 30 years; 79 cases reported were in patients 16 or 17 years old.
- The vast majority (81%) of the 270 patients younger than 30 years who were discharged from care after suspected myocarditis related to COVID-19 vaccination have recovered fully; the remaining 19% of patients report ongoing symptoms or complete data are missing.
- 196 cases of suspected myocarditis after a COVID-19 vaccine were reported in young adults 18 to 24 years of age, which is higher than expected for this age group.
As of May 31, only about 9% of the COVID-19 vaccine doses administered were to people 16 to 24 years of age, which is why this “higher-than-normal rate of possible myocarditis cases” warrants investigation, the AHA/ASA says.
They note that these suspected myocarditis cases were reported to VAERS because of their proximity to COVID-19 vaccine administration.
It remains to be determined which cases meet the clinical criteria for a diagnosis of myocarditis and whether they have any direct connection to the COVID-19 vaccine, the AHA/ASA says.
They urge all health care professionals to be aware of “very rare” adverse events that could be related to a COVID-19 vaccine, including myocarditis, blood clots, low platelets, and symptoms of severe inflammation.
They advise asking patients who present with symptoms related to these conditions about the timing of recent COVID vaccinations, as needed, to confirm the diagnosis and provide appropriate treatment quickly.
The AHA will be at the CDC’s June 18 meeting to review the latest evidence on cases of suspected myocarditis after the COVID-19 vaccine, the statement adds.
The statement notes that it reflects the views of the AHA/ASA and its scientific leadership, including current president Mitchel S.V. Elkind, MD, PhD; immediate past-president Robert A. Harrington, MD; president-elect Donald M. Lloyd-Jones, MD; AHA/ASA chief science and medical officer Mariell Jessup, MD; and chief medical officer for prevention Eduardo Sanchez, MD, MPH.
A version of this article first appeared on Medscape.com.
20-year-old woman • 2 syncopal episodes • nausea • dizziness • Dx?
THE CASE
A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.
The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.
The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.
Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).
THE DIAGNOSIS
An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.
DISCUSSION
POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.1
The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.
Continue to: Syncope could indicate a larger cardiovascular problem
Syncope could indicate a larger cardiovascular problem
The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.
Unintended adverse effects
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.4 However, case reports have shown an association between SSRIs and syncope.4-6 SSRIs have also been tied to increased heart rate variability.7
Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.
Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.
THE TAKEAWAY
We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.
CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; courtney.dominguez@duke.edu
1. Ojha A, McNeeley K, Heller E, et al. Orthostatic syndromes differ in syncope frequency. Am J Med. 2010;123:245-249. doi: 10.1016/j.amjmed.2009.09.018
2. Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome—diagnosis, physiology, and prognosis. Auton Neurosci. 2018;215:3-11. doi: 10.1016/j.autneu.2018.02.005
3. Fedorowski A. Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management. J Intern Med. 2018;285:352-366. doi:10.1111/joim.12852
4. Pacher P, Ungvari Z, Kecskemeti V, et al. Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants. Curr Med Chem. 1998;5:381-390.
5. Feder R. Bradycardia and syncope induced by fluoxetine. J Clin Psychiatry. 1991;52:139.
6. Ellison JM, Milofsky JE, Ely E. Fluoxetine-induced bradycardia and syncope in two patients. J Clin Psychiatry. 1990;51:385-386.
7. Tucker P, Adamson P, Miranda R Jr, et al. Paroxetine increases heart rate variability in panic disorder. J Clin Psychopharmacol. 1997;17:370-376. doi: 10.1097/00004714-199710000-00006
THE CASE
A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.
The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.
The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.
Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).
THE DIAGNOSIS
An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.
DISCUSSION
POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.1
The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.
Continue to: Syncope could indicate a larger cardiovascular problem
Syncope could indicate a larger cardiovascular problem
The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.
Unintended adverse effects
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.4 However, case reports have shown an association between SSRIs and syncope.4-6 SSRIs have also been tied to increased heart rate variability.7
Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.
Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.
THE TAKEAWAY
We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.
CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; courtney.dominguez@duke.edu
THE CASE
A 20-year-old woman presented to clinic with a chief complaint of 2 syncopal episodes within 10 minutes of each other. She reported that in both cases, she felt nauseated and dizzy before losing consciousness. She lost consciousness for a few seconds during the first episode and a few minutes during the second episode. Both episodes were unwitnessed.
The patient denied any fasting, vomiting, diarrhea, palpitations, chest pain, incontinence, oral trauma, headaches, fevers, chills, or tremors. Her last menstrual period started 3 days prior to presentation. The patient was taking sertraline 25 mg once daily for anxiety and depression and norethindrone acetate–ethinyl estradiol tablets 20 µg daily for birth control. She also was finishing a 7-day course of metronidazole for bacterial vaginosis. She reported having started the sertraline about 10 days prior to the syncopal episodes. She denied any personal history of drug or alcohol use, syncope, seizures, or any other medical conditions. Family history was negative for any cardiac or neurologic conditions.
The patient appeared euvolemic on exam. Overall, the review of the respiratory, cardiac, and neurologic systems was unremarkable. An electrocardiogram, obtained in clinic, showed a normal sinus rhythm and QT interval. Orthostatic blood pressure and heart rate measurements were as follows: supine, 122/83 mm Hg and 67 beats/min; seated, 118/87 mm Hg and 60 beats/min; and standing, 123/83 mm Hg and 95 beats/min. In addition to the increase in pulse between sitting and standing, the patient reported feeling nauseated when transitioning to a standing position.
Laboratory work-up included a comprehensive metabolic panel, complete blood count, and thyroid-stimulating hormone test. The results showed mild erythrocytosis with a hematocrit and hemoglobin of 46.1% and 15.6 g/dL respectively, as well as mild hypercalcemia (10.4 mg/dL).
THE DIAGNOSIS
An increase in heart rate of more than 30 beats/min when the patient went from a sitting to a standing position pointed to a diagnosis of postural orthostatic tachycardia syndrome (POTS). This prompted us to stop the sertraline.
DISCUSSION
POTS is a type of intolerance to orthostasis related to a significant increase in pulse without resulting hypotension upon standing. Other symptoms that accompany this change in position include dizziness, lightheadedness, blurry vision, and fatigue. Syncope occurs in about 40% of patients with POTS, which may be more frequent than for patients with orthostatic hypotension.1
The overall prevalence of POTS is 0.2% to 1%; however, it is generally seen in a 5:1 female-to-male ratio.2,3 POTS is often idiopathic. That said, it can also be caused by medication adverse effects, hypovolemia, and stressors, including vaccinations, viral infections, trauma, and emotional triggers. On physical exam, this patient did not appear to be hypovolemic, and she reported normal oral intake prior to this visit. Since the patient had started taking sertraline about 10 days prior to her syncopal episodes, we suspected POTS secondary to sertraline use was the likely etiology in this otherwise healthy young woman.
Continue to: Syncope could indicate a larger cardiovascular problem
Syncope could indicate a larger cardiovascular problem
The differential diagnosis of dizziness with loss of consciousness includes anemia, vasovagal syncope, orthostatic hypotension, dehydration, electrolyte imbalance, arrhythmia, prolonged QT syndrome, cardiac valve or structure abnormality, and seizure. Most of these differentials can be ruled out from basic laboratory tests or cardiac imaging. In POTS, the diagnostic work-up is essentially normal compared to other causes of syncope. Orthostatic hypotension, for example, is similar; however, there is an additional change in the arterial blood pressure.
Unintended adverse effects
Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, are known to have fewer cardiovascular adverse effects compared to older antidepressants such as tricyclic antidepressants and monoamine oxidase inhibitors.4 However, case reports have shown an association between SSRIs and syncope.4-6 SSRIs have also been tied to increased heart rate variability.7
Nearly 2 weeks after stopping sertraline, our patient presented to clinic and was given a diagnosis of streptococcal pharyngitis. She said she’d had no additional syncopal episodes. Twenty days after sertraline cessation, the patient returned for follow-up. Her blood pressure and heart rate were as follows: supine, 112/68 mm Hg and 61 beats/min; seated, 113/74 mm Hg and 87 beats/min; and standing, 108/74 mm Hg and 78 beats/min.
Thus, after cessation of sertraline, her orthostatic heart rate changes were smaller than when she was first examined. Her vital signs showed an increase in pulse of 26 beats/min between lying and sitting, without any reports of nausea. She had no further complaints of dizziness or syncopal episodes.
THE TAKEAWAY
We don’t always know how a patient will respond to a newly prescribed medication or lifestyle change. A proper review of a patient’s history and medication use is a pivotal first step in making any diagnosis.
CORRESPONDENCE
Courtney Lynn Dominguez, MD, 4220 North Roxboro Street, Durham, NC 27704; courtney.dominguez@duke.edu
1. Ojha A, McNeeley K, Heller E, et al. Orthostatic syndromes differ in syncope frequency. Am J Med. 2010;123:245-249. doi: 10.1016/j.amjmed.2009.09.018
2. Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome—diagnosis, physiology, and prognosis. Auton Neurosci. 2018;215:3-11. doi: 10.1016/j.autneu.2018.02.005
3. Fedorowski A. Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management. J Intern Med. 2018;285:352-366. doi:10.1111/joim.12852
4. Pacher P, Ungvari Z, Kecskemeti V, et al. Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants. Curr Med Chem. 1998;5:381-390.
5. Feder R. Bradycardia and syncope induced by fluoxetine. J Clin Psychiatry. 1991;52:139.
6. Ellison JM, Milofsky JE, Ely E. Fluoxetine-induced bradycardia and syncope in two patients. J Clin Psychiatry. 1990;51:385-386.
7. Tucker P, Adamson P, Miranda R Jr, et al. Paroxetine increases heart rate variability in panic disorder. J Clin Psychopharmacol. 1997;17:370-376. doi: 10.1097/00004714-199710000-00006
1. Ojha A, McNeeley K, Heller E, et al. Orthostatic syndromes differ in syncope frequency. Am J Med. 2010;123:245-249. doi: 10.1016/j.amjmed.2009.09.018
2. Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome—diagnosis, physiology, and prognosis. Auton Neurosci. 2018;215:3-11. doi: 10.1016/j.autneu.2018.02.005
3. Fedorowski A. Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management. J Intern Med. 2018;285:352-366. doi:10.1111/joim.12852
4. Pacher P, Ungvari Z, Kecskemeti V, et al. Review of cardiovascular effects of fluoxetine, a selective serotonin reuptake inhibitor, compared to tricyclic antidepressants. Curr Med Chem. 1998;5:381-390.
5. Feder R. Bradycardia and syncope induced by fluoxetine. J Clin Psychiatry. 1991;52:139.
6. Ellison JM, Milofsky JE, Ely E. Fluoxetine-induced bradycardia and syncope in two patients. J Clin Psychiatry. 1990;51:385-386.
7. Tucker P, Adamson P, Miranda R Jr, et al. Paroxetine increases heart rate variability in panic disorder. J Clin Psychopharmacol. 1997;17:370-376. doi: 10.1097/00004714-199710000-00006
Getting hypertension under control in the youngest of patients
Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5
In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7
As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.
First step: Identifying hypertension
Risk factors
Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16
Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13
Recommendations for screening and measuring BP
The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:
- annually in all children ≥ 3 years of age
- at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6
Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.
Continue to: When an initial reading...
When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18
TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.
TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.
Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.
ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.
Continue to: Home monitoring
Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6
Evaluating hypertension in children and adolescents
Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.
Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6
Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6
Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20
Continue to: Important aspects...
Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.
The family history should include notation of first- and second-degree relatives with hypertension.6
Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22
The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6
Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.
Continue to: Testing
Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing.
TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.
Mapping out the treatment plan
Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25
Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.
Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:
- treatment-resistant hypertension
- stage 2 hypertension that is not quickly responsive to initial treatment
- an identified secondary cause of hypertension.
Continue to: Lifestyle modification can make a big difference
Lifestyle modification can make a big difference
Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30
Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34
Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25
Proceed with pharmacotherapy when these criteria are met
Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:
- once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
- stage 2 hypertension without a modifiable risk factor, such as obesity
- any stage of hypertension with comorbid CKD, DM, or proteinuria
- target-organ damage, such as left ventricular hypertrophy
- symptomatic hypertension.6,29
There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:
- angiotensin-converting enzyme (ACE) inhibitors
- angiotensin receptor blockers (ARBs)
- calcium-channel blockers (CCBs)
- thiazide diuretics.
Continue to: For a child with known CKD...
For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.
Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.
If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6
Restrict activities—or not?
There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).
aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.
CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com
1. Theodore RF, Broadbent J, Nagin D, et al. Childhood to early-midlife systolic blood pressure trajectories: early-life predictors, effect modifiers, and adult cardiovascular outcomes. Hypertension. 2015;66:1108-1115. doi: 10.1161/HYPERTENSIONAHA.115.05831
2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039
3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005
4. Ippisch HM, Daniels SR. Hypertension in overweight and obese children. Prog Pediatr Cardiol. 2008;25:177-182. doi: org/10.1016/j.ppedcard.2008.05.002
5. Urbina EM, Lande MB, Hooper SR, et al. Target organ abnormalities in pediatric hypertension. J Pediatr. 2018;202:14-22. doi: 10.1016/j.jpeds.2018.07.026
6. Flynn JT, Kaelber DC, Baker-Smith CM, et al; . Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. doi: 10.1542/peds.2017-1904
7. Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018;142:e20180245. doi: 10.1542/peds.2018-0245
8. Falkner B, Gidding SS, Ramirez-Garnica G, et al. The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr. 2006;148:195-200. doi: 10.1016/j.jpeds.2005.10.030
9. Rodriguez BL, Dabelea D, Liese AD, et al; SEARCH Study Group. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245-251.e1. doi: 10.1016/j.jpeds.2010.02.021
10. Shay CM, Ning H, Daniels SR, et al. Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010. Circulation. 2013;127:1369-1376. doi: 10.1161/CIRCULATIONAHA.113.001559
11. Archbold KH, Vasquez MM, Goodwin JL, et al. Effects of sleep patterns and obesity on increases in blood pressure in a 5-year period: report from the Tucson Children’s Assessment of Sleep Apnea Study. J Pediatr. 2012;161:26-30. doi: 10.1016/j.jpeds.2011.12.034
12. Flynn JT, Mitsnefes M, Pierce C, et al; . Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52:631-637. doi: 10.1161/HYPERTENSIONAHA.108.110635
13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE
14. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med. 2000;342:256-263. doi: 10.1056/NEJM200001273420407
15. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008;117:3171-3180. doi: 10.1161/CIRCULATIONAHA.107.730366
16. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics. 2007;119:237-246. doi: 10.1542/peds.2006-2543
17. Parker ED, Sinaiko AR, Kharbanda EO, et al. Change in weight status and development of hypertension. Pediatrics. 2016; 137:e20151662. doi: 10.1542/peds.2015-1662
18. Pickering TG, Hall JE, Appel LJ, et al; . Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142-161. doi: 10.1161/01.HYP.0000150859.47929.8e
19. Staley JR, Bradley J, Silverwood RJ, et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study. J Am Heart Assoc. 2015;4:e001422. doi: 10.1161/JAHA.114.001422
20. Yang Q, Zhang Z, Zuklina EV, et al. Sodium intake and blood pressure among US children and adolescents. Pediatrics. 2012;130:611-619. doi: 10.1542/peds.2011-3870
21. Le-Ha C, Beilin LJ, Burrows S, et al. Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence. Eur J Prev Cardiol. 2013;20:947-955. doi: 10.1177/2047487312452966
22. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006;21:92-95. doi: 10.1007/s00467-005-2051-1
23. Wiesen J, Adkins M, Fortune S, et al. Evaluation of pediatric patients with mild-to-moderate hypertension: yield of diagnostic testing. Pediatrics. 2008;122:e988-993. doi: 10.1542/peds.2008-0365
24. Kapur G, Ahmed M, Pan C, et al. Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report. J Clin Hypertens (Greenwich). 2010;12:34-39. doi: 10.1111/j.1751-7176.2009.00195.x
25. Anyaegbu EI, Dharnidharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61:131-151. doi: 10.1016/j.pcl.2013.09.011
26. Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medical setting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-653. doi: 10.1016/j.chc.2012.05.013
27. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54:2396-2406. doi: 10.1016/j.jacc.2009.08.030
28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113
29. Singer PS. Updates on hypertension and new guidelines. Adv Pediatr. 2019;66:177-187. doi: 10.1016/j.yapd.2019.03.009
30. Torrance B, McGuire KA, Lewanczuk R, et al. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag. 2007;3:139-149.
31. DASH eating plan. National Heart, Lung, and Blood Institute. Accessed April 26, 2021. www.nhlbi.nih.gov/health-topics/dash-eating-plan
32. Nutritional goals for age-sex groups based on dietary reference intakes and dietary guidelines recommendations (Appendix 7). In: US Department of Agriculture. Dietary guidelines for Americans, 2015-2020. 8th ed. December 2015;97-98. Accessed April 26, 2021. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf
33. Asghari G, Yuzbashian E, Mirmiran P, et al. Dietary Approaches to Stop Hypertension (DASH) dietary pattern is associated with reduced incidence of metabolic syndrome in children and adolescents. J Pediatr. 2016;174:178-184.e1. doi: 10.1016/j.jpeds.2016.03.077
34. Damasceno MMC, de Araújo MFM, de Freitas RWJF, et al. The association between blood pressure in adolescents and the consumption of fruits, vegetables and fruit juice–an exploratory study. J Clin Nurs. 2011;20:1553-1560. doi: 10.1111/j.1365-2702.2010.03608.x
35. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N Am. 2018;27:63-76. doi: 10.1016/j.chc.2017.08.003
36. Kumar S, King EC, Christison, et al; POWER Work Group. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr. 2019;208:57-65.e4. doi: 10.1016/j.jpeds.2018.12.049
37. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills® Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health. 2011;48:59-64. doi: 10.1016/j.jadohealth.2010.05.019
38. Escape Trial Group; E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639-1650. doi: 10.1056/NEJMoa0902066
Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5
In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7
As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.
First step: Identifying hypertension
Risk factors
Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16
Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13
Recommendations for screening and measuring BP
The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:
- annually in all children ≥ 3 years of age
- at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6
Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.
Continue to: When an initial reading...
When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18
TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.
TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.
Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.
ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.
Continue to: Home monitoring
Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6
Evaluating hypertension in children and adolescents
Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.
Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6
Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6
Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20
Continue to: Important aspects...
Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.
The family history should include notation of first- and second-degree relatives with hypertension.6
Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22
The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6
Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.
Continue to: Testing
Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing.
TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.
Mapping out the treatment plan
Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25
Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.
Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:
- treatment-resistant hypertension
- stage 2 hypertension that is not quickly responsive to initial treatment
- an identified secondary cause of hypertension.
Continue to: Lifestyle modification can make a big difference
Lifestyle modification can make a big difference
Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30
Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34
Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25
Proceed with pharmacotherapy when these criteria are met
Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:
- once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
- stage 2 hypertension without a modifiable risk factor, such as obesity
- any stage of hypertension with comorbid CKD, DM, or proteinuria
- target-organ damage, such as left ventricular hypertrophy
- symptomatic hypertension.6,29
There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:
- angiotensin-converting enzyme (ACE) inhibitors
- angiotensin receptor blockers (ARBs)
- calcium-channel blockers (CCBs)
- thiazide diuretics.
Continue to: For a child with known CKD...
For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.
Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.
If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6
Restrict activities—or not?
There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).
aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.
CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com
Hypertension and elevated blood pressure (BP) in children and adolescents correlate to hypertension in adults, insofar as complications and medical therapy increase with age.1,2 Untreated, hypertension in children and adolescents can result in multiple harmful physiologic changes, including left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, arterial stiffening, endothelial dysfunction, and neurocognitive deficits.3-5
In 2017, the American Academy of Pediatrics (AAP) published clinical practice guidelines for the diagnosis and management of elevated BP and hypertension in children and adolescentsa (TABLE 16). Applying the definition of elevated BP set out in these guidelines yielded a 13% prevalence of hypertension in a cohort of subjects 10 to 18 years of age with comorbid obesity and diabetes mellitus (DM). AAP guideline definitions also improved the sensitivity for identifying hypertensive end-organ damage.7
As the prevalence of hypertension increases, screening for and accurate diagnosis of this condition in children are becoming more important. Recognition and management remain a vital part of primary care. In this article, we review the updated guidance on diagnosis and treatment, including lifestyle modification and pharmacotherapy.
First step: Identifying hypertension
Risk factors
Risk factors for pediatric hypertension are similar to those in adults. These include obesity (body mass index ≥ 95th percentile for age), types 1 and 2 DM, elevated sodium intake, sleep-disordered breathing, and chronic kidney disease (CKD). Some risk factors, such as premature birth and coarctation of the aorta, are specific to the pediatric population.8-14 Pediatric obesity strongly correlates with both pediatric and adult hypertension, and accelerated weight gain might increase the risk of elevated BP in adulthood.15,16
Intervening early to mitigate or eliminate some of these modifiable risk factors can prevent or treat hypertension.17 Alternatively, having been breastfed as an infant has been reliably shown to reduce the risk of elevated BP in children.13
Recommendations for screening and measuring BP
The optimal age to start measuring BP is not clearly defined. AAP recommends measurement:
- annually in all children ≥ 3 years of age
- at every encounter in patients who have a specific comorbid condition, including obesity, DM, renal disease, and aortic-arch abnormalities (obstruction and coarctation) and in those who are taking medication known to increase BP.6
Protocol. Measure BP in the right arm for consistency and comparison with reference values. The width of the cuff bladder should be at least 40%, and the length, 80% to 100%, of arm circumference. Position the cuff bladder midway between the olecranon and acromion. Obtain the measurement in a quiet and comfortable environment after the patient has rested for 3 to 5 minutes. The patient should be seated, preferably with feet on the floor; elbows should be supported at the level of the heart.
Continue to: When an initial reading...
When an initial reading is elevated, whether by oscillometric or auscultatory measurement, 2 more auscultatory BP measurements should be taken during the same visit; these measurements are averaged to determine the BP category.18
TABLE 16 defines BP categories based on age, sex, and height. We recommend using the free resource MD Calc (www.mdcalc.com/aap-pediatric-hypertension-guidelines) to assist in calculating the BP category.
TABLE 26 describes the timing of follow-up based on the initial BP reading and diagnosis.
Ambulatory BP monitoring (ABPM) is a validated device that measures BP every 20 to 30 minutes throughout the day and night. ABPM should be performed initially in all patients with persistently elevated BP and routinely in children and adolescents with a high-risk comorbidity (TABLE 26). Note: Insurance coverage of ABPM is limited.
ABPM is also used to diagnose so-called white-coat hypertension, defined as BP ≥ 95th percentile for age, sex, and height in the clinic setting but < 95th percentile during ABPM. This phenomenon can be challenging to diagnose.
Continue to: Home monitoring
Home monitoring. Do not use home BP monitoring to establish a diagnosis of hypertension, although one of these devices can be used as an adjunct to office and ambulatory BP monitoring after the diagnosis has been made.6
Evaluating hypertension in children and adolescents
Once a diagnosis of hypertension has been made, undertake a thorough history, physical examination, and diagnostic testing to evaluate for possible causes, comorbidities, and any evidence of end-organ damage.
Comprehensive history. Pertinent aspects include perinatal, nutritional, physical activity, psychosocial, family, medication—and of course, medical—histories.6
Maternal elevated BP or hypertension is related to an offspring’s elevated BP in childhood and adolescence.19 Other pertinent aspects of the perinatal history include complications of pregnancy, gestational age, birth weight, and neonatal complications.6
Nutritional and physical activity histories can highlight contributing factors in the development of hypertension and can be a guide to recommending lifestyle modifications.6 Sodium intake, which influences BP, should be part of the nutritional history.20
Continue to: Important aspects...
Important aspects of the psychosocial history include feelings of depression or anxiety, bullying, and body perception. Children older than 10 years should be asked about smoking, alcohol, and other substance use.
The family history should include notation of first- and second-degree relatives with hypertension.6
Inquire about medications that can raise BP, including oral contraceptives, which are commonly prescribed in this population.21,22
The physical exam should include measured height and weight, with calculation of the body mass index percentile for age; of note, obesity is strongly associated with hypertension, and poor growth might signal underlying chronic disease. Once elevated BP has been confirmed, the exam should include measurement of BP in both arms and in a leg (TABLE 26). BP that is lower in the leg than in the arms (in any given patient, BP readings in the legs are usually higher than in the arms), or weak or absent femoral pulses, suggest coarctation of the aorta.6
Focus the balance of the physical exam on physical findings that suggest secondary causes of hypertension or evidence of end-organ damage.
Continue to: Testing
Testing. TABLE 36,23 summarizes the diagnostic testing recommended for all children and for specific populations; TABLE 26 indicates when to obtain diagnostic testing.
TABLE 42,12,13,24 outlines the basis of primary and of secondary hypertension and common historical and physical findings that suggest a secondary cause.
Mapping out the treatment plan
Pediatric hypertension should be treated in patients with stage 1 or higher hypertension.6 This threshold for therapy is based on evidence that reducing BP below a goal of (1) the 90th percentile (calculated based on age, sex, and height) in children up to 12 years of age or (2) of < 130/80 mm Hg for children ≥ 13 years reduces short- and long-term morbidity and mortality.5,6,25
Choice of initial treatment depends on the severity of BP elevation and the presence of comorbidities (FIGURE6,20,25-28). The initial, fundamental treatment recommendation is lifestyle modification,6,29 including regular physical exercise, a change in nutritional habits, weight loss (because obesity is a common comorbid condition), elimination of tobacco and substance use, and stress reduction.25,26 Medications can be used as well, along with other treatments for specific causes of secondary hypertension.
Referral to a specialist can be considered if consultation for assistance with treatment is preferred (TABLE 26) or if the patient has:
- treatment-resistant hypertension
- stage 2 hypertension that is not quickly responsive to initial treatment
- an identified secondary cause of hypertension.
Continue to: Lifestyle modification can make a big difference
Lifestyle modification can make a big difference
Exercise. “Regular” physical exercise for children to reduce BP is defined as ≥ 30 to 60 minutes of active play daily.6,29 Studies have shown significant improvement not only in BP but also in other cardiovascular disease risk parameters with regular physical exercise.27 A study found that the reduction in systolic BP is, on average, approximately 6 mm Hg with physical activity alone.30
Nutrition. DASH—Dietary Approaches to Stop Hypertension—is an evidence-based program to reduce BP. This nutritional guideline focuses on a diet rich in natural foods, including fruits, vegetables, minimally processed carbohydrates and whole grains, and low-fat dairy and meats. It also emphasizes the importance of avoiding foods high in processed sugars and reducing sodium intake.31 Higher-than-recommended sodium intake, based on age and sex (and established as part of dietary recommendations for children on the US Department of Health and Human Services’ website health.gov) directly correlates with the risk of prehypertension and hypertension—especially in overweight and obese children.20,32 DASH has been shown to reliably reduce the incidence of hypertension in children; other studies have supported increased intake of fruits, vegetables, and legumes as strategies to reduce BP.33,34
Other interventions. Techniques to improve adherence to exercise and nutritional modifications for children include motivational interviewing, community programs and education, and family counseling.27,35 A recent study showed that a community-based lifestyle modification program that is focused on weight loss in obese children resulted in a significant reduction in BP values at higher stages of obesity.36 There is evidence that techniques such as controlled breathing and meditation can reduce BP.37 Last, screening and counseling to encourage tobacco and substance use discontinuation are recommended for children and adolescents to improve health outcomes.25
Proceed with pharmacotherapy when these criteria are met
Medical therapy is recommended when certain criteria are met, although this decision should be individualized and made in agreement by the treating physician, patient, and family. These criteria (FIGURE6,20,25-28) are6,29:
- once a diagnosis of stage 1 hypertension has been established, failure to meet a BP goal after 3 to 6 months of attempting lifestyle modifications
- stage 2 hypertension without a modifiable risk factor, such as obesity
- any stage of hypertension with comorbid CKD, DM, or proteinuria
- target-organ damage, such as left ventricular hypertrophy
- symptomatic hypertension.6,29
There are circumstances in which one or another specific antihypertensive agent is recommended for children; however, for most patients with primary hypertension, the following classes are recommended for first-line use6,22:
- angiotensin-converting enzyme (ACE) inhibitors
- angiotensin receptor blockers (ARBs)
- calcium-channel blockers (CCBs)
- thiazide diuretics.
Continue to: For a child with known CKD...
For a child with known CKD, DM, or proteinuria, an ACE inhibitor or ARB is beneficial as first-line therapy.38 Because ACE inhibitors and ARBs have teratogenic effects, however, a thorough review of fertility status is recommended for female patients before any of these agents are started. CCBs and thiazides are typically recommended as first-line agents for Black patients.6,28 Beta-blockers are typically avoided in the first line because of their adverse effect profile.
Most antihypertensive medications can be titrated every 1 or 2 weeks; the patient’s BP can be monitored with a home BP cuff to track the effect of titration. In general, the patient should be seen for follow-up every 4 to 6 weeks for a BP recheck and review of medication tolerance and adverse effects. Once the treatment goal is achieved, it is reasonable to have the patient return every 3 to 6 months to reassess the treatment plan.
If the BP goal is difficult to achieve despite titration of medication and lifestyle changes, consider repeat ABPM assessment, a specialty referral, or both. It is reasonable for children who have been started on medication and have adhered to lifestyle modifications to practice a “step-down” approach to discontinuing medication; this approach can also be considered once any secondary cause has been corrected. Any target-organ abnormalities identified at diagnosis (eg, proteinuria, CKD, left ventricular hypertrophy) need to be reexamined at follow-up.6
Restrict activities—or not?
There is evidence that a child with stage 1 or well-controlled stage 2 hypertension without evidence of end-organ damage should not have restrictions on sports or activity. However, in uncontrolled stage 2 hypertension or when evidence of target end-organ damage is present, you should advise against participation in highly competitive sports and highly static sports (eg, weightlifting, wrestling), based on expert opinion6,25 (FIGURE6,20,25-28).
aAAP guidelines on the management of pediatric hypertension vary from those of the US Preventive Services Task Force. See the Practice Alert, “A review of the latest USPSTF recommendations,” in the May 2021 issue.
CORRESPONDENCE
Dustin K. Smith, MD, Family Medicine Department, 2080 Child Street, Jacksonville, FL, 32214; dustinksmith@yahoo.com
1. Theodore RF, Broadbent J, Nagin D, et al. Childhood to early-midlife systolic blood pressure trajectories: early-life predictors, effect modifiers, and adult cardiovascular outcomes. Hypertension. 2015;66:1108-1115. doi: 10.1161/HYPERTENSIONAHA.115.05831
2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039
3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005
4. Ippisch HM, Daniels SR. Hypertension in overweight and obese children. Prog Pediatr Cardiol. 2008;25:177-182. doi: org/10.1016/j.ppedcard.2008.05.002
5. Urbina EM, Lande MB, Hooper SR, et al. Target organ abnormalities in pediatric hypertension. J Pediatr. 2018;202:14-22. doi: 10.1016/j.jpeds.2018.07.026
6. Flynn JT, Kaelber DC, Baker-Smith CM, et al; . Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. doi: 10.1542/peds.2017-1904
7. Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018;142:e20180245. doi: 10.1542/peds.2018-0245
8. Falkner B, Gidding SS, Ramirez-Garnica G, et al. The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr. 2006;148:195-200. doi: 10.1016/j.jpeds.2005.10.030
9. Rodriguez BL, Dabelea D, Liese AD, et al; SEARCH Study Group. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245-251.e1. doi: 10.1016/j.jpeds.2010.02.021
10. Shay CM, Ning H, Daniels SR, et al. Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010. Circulation. 2013;127:1369-1376. doi: 10.1161/CIRCULATIONAHA.113.001559
11. Archbold KH, Vasquez MM, Goodwin JL, et al. Effects of sleep patterns and obesity on increases in blood pressure in a 5-year period: report from the Tucson Children’s Assessment of Sleep Apnea Study. J Pediatr. 2012;161:26-30. doi: 10.1016/j.jpeds.2011.12.034
12. Flynn JT, Mitsnefes M, Pierce C, et al; . Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52:631-637. doi: 10.1161/HYPERTENSIONAHA.108.110635
13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE
14. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med. 2000;342:256-263. doi: 10.1056/NEJM200001273420407
15. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008;117:3171-3180. doi: 10.1161/CIRCULATIONAHA.107.730366
16. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics. 2007;119:237-246. doi: 10.1542/peds.2006-2543
17. Parker ED, Sinaiko AR, Kharbanda EO, et al. Change in weight status and development of hypertension. Pediatrics. 2016; 137:e20151662. doi: 10.1542/peds.2015-1662
18. Pickering TG, Hall JE, Appel LJ, et al; . Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142-161. doi: 10.1161/01.HYP.0000150859.47929.8e
19. Staley JR, Bradley J, Silverwood RJ, et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study. J Am Heart Assoc. 2015;4:e001422. doi: 10.1161/JAHA.114.001422
20. Yang Q, Zhang Z, Zuklina EV, et al. Sodium intake and blood pressure among US children and adolescents. Pediatrics. 2012;130:611-619. doi: 10.1542/peds.2011-3870
21. Le-Ha C, Beilin LJ, Burrows S, et al. Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence. Eur J Prev Cardiol. 2013;20:947-955. doi: 10.1177/2047487312452966
22. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006;21:92-95. doi: 10.1007/s00467-005-2051-1
23. Wiesen J, Adkins M, Fortune S, et al. Evaluation of pediatric patients with mild-to-moderate hypertension: yield of diagnostic testing. Pediatrics. 2008;122:e988-993. doi: 10.1542/peds.2008-0365
24. Kapur G, Ahmed M, Pan C, et al. Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report. J Clin Hypertens (Greenwich). 2010;12:34-39. doi: 10.1111/j.1751-7176.2009.00195.x
25. Anyaegbu EI, Dharnidharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61:131-151. doi: 10.1016/j.pcl.2013.09.011
26. Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medical setting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-653. doi: 10.1016/j.chc.2012.05.013
27. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54:2396-2406. doi: 10.1016/j.jacc.2009.08.030
28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113
29. Singer PS. Updates on hypertension and new guidelines. Adv Pediatr. 2019;66:177-187. doi: 10.1016/j.yapd.2019.03.009
30. Torrance B, McGuire KA, Lewanczuk R, et al. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag. 2007;3:139-149.
31. DASH eating plan. National Heart, Lung, and Blood Institute. Accessed April 26, 2021. www.nhlbi.nih.gov/health-topics/dash-eating-plan
32. Nutritional goals for age-sex groups based on dietary reference intakes and dietary guidelines recommendations (Appendix 7). In: US Department of Agriculture. Dietary guidelines for Americans, 2015-2020. 8th ed. December 2015;97-98. Accessed April 26, 2021. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf
33. Asghari G, Yuzbashian E, Mirmiran P, et al. Dietary Approaches to Stop Hypertension (DASH) dietary pattern is associated with reduced incidence of metabolic syndrome in children and adolescents. J Pediatr. 2016;174:178-184.e1. doi: 10.1016/j.jpeds.2016.03.077
34. Damasceno MMC, de Araújo MFM, de Freitas RWJF, et al. The association between blood pressure in adolescents and the consumption of fruits, vegetables and fruit juice–an exploratory study. J Clin Nurs. 2011;20:1553-1560. doi: 10.1111/j.1365-2702.2010.03608.x
35. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N Am. 2018;27:63-76. doi: 10.1016/j.chc.2017.08.003
36. Kumar S, King EC, Christison, et al; POWER Work Group. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr. 2019;208:57-65.e4. doi: 10.1016/j.jpeds.2018.12.049
37. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills® Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health. 2011;48:59-64. doi: 10.1016/j.jadohealth.2010.05.019
38. Escape Trial Group; E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639-1650. doi: 10.1056/NEJMoa0902066
1. Theodore RF, Broadbent J, Nagin D, et al. Childhood to early-midlife systolic blood pressure trajectories: early-life predictors, effect modifiers, and adult cardiovascular outcomes. Hypertension. 2015;66:1108-1115. doi: 10.1161/HYPERTENSIONAHA.115.05831
2. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34:1887-1920. doi: 10.1097/HJH.0000000000001039
3. Weaver DJ, Mitsnefes MM. Effects of systemic hypertension on the cardiovascular system. Prog Pediatr Cardiol. 2016;41:59-65. https://doi.org/10.1016/j.ppedcard.2015.11.005
4. Ippisch HM, Daniels SR. Hypertension in overweight and obese children. Prog Pediatr Cardiol. 2008;25:177-182. doi: org/10.1016/j.ppedcard.2008.05.002
5. Urbina EM, Lande MB, Hooper SR, et al. Target organ abnormalities in pediatric hypertension. J Pediatr. 2018;202:14-22. doi: 10.1016/j.jpeds.2018.07.026
6. Flynn JT, Kaelber DC, Baker-Smith CM, et al; . Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904. doi: 10.1542/peds.2017-1904
7. Khoury M, Khoury PR, Dolan LM, et al. Clinical implications of the revised AAP pediatric hypertension guidelines. Pediatrics. 2018;142:e20180245. doi: 10.1542/peds.2018-0245
8. Falkner B, Gidding SS, Ramirez-Garnica G, et al. The relationship of body mass index and blood pressure in primary care pediatric patients. J Pediatr. 2006;148:195-200. doi: 10.1016/j.jpeds.2005.10.030
9. Rodriguez BL, Dabelea D, Liese AD, et al; SEARCH Study Group. Prevalence and correlates of elevated blood pressure in youth with diabetes mellitus: the SEARCH for diabetes in youth study. J Pediatr. 2010;157:245-251.e1. doi: 10.1016/j.jpeds.2010.02.021
10. Shay CM, Ning H, Daniels SR, et al. Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010. Circulation. 2013;127:1369-1376. doi: 10.1161/CIRCULATIONAHA.113.001559
11. Archbold KH, Vasquez MM, Goodwin JL, et al. Effects of sleep patterns and obesity on increases in blood pressure in a 5-year period: report from the Tucson Children’s Assessment of Sleep Apnea Study. J Pediatr. 2012;161:26-30. doi: 10.1016/j.jpeds.2011.12.034
12. Flynn JT, Mitsnefes M, Pierce C, et al; . Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension. 2008;52:631-637. doi: 10.1161/HYPERTENSIONAHA.108.110635
13. Martin RM, Ness AR, Gunnell D, et al; ALSPAC Study Team. Does breast-feeding in infancy lower blood pressure in childhood? The Avon Longitudinal Study of Parents and Children (ALSPAC). Circulation. 2004;109:1259-1266. doi: 10.1161/01.CIR.0000118468.76447.CE
14. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. N Engl J Med. 2000;342:256-263. doi: 10.1056/NEJM200001273420407
15. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008;117:3171-3180. doi: 10.1161/CIRCULATIONAHA.107.730366
16. Sun SS, Grave GD, Siervogel RM, et al. Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life. Pediatrics. 2007;119:237-246. doi: 10.1542/peds.2006-2543
17. Parker ED, Sinaiko AR, Kharbanda EO, et al. Change in weight status and development of hypertension. Pediatrics. 2016; 137:e20151662. doi: 10.1542/peds.2015-1662
18. Pickering TG, Hall JE, Appel LJ, et al; . Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005;45:142-161. doi: 10.1161/01.HYP.0000150859.47929.8e
19. Staley JR, Bradley J, Silverwood RJ, et al. Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study. J Am Heart Assoc. 2015;4:e001422. doi: 10.1161/JAHA.114.001422
20. Yang Q, Zhang Z, Zuklina EV, et al. Sodium intake and blood pressure among US children and adolescents. Pediatrics. 2012;130:611-619. doi: 10.1542/peds.2011-3870
21. Le-Ha C, Beilin LJ, Burrows S, et al. Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence. Eur J Prev Cardiol. 2013;20:947-955. doi: 10.1177/2047487312452966
22. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006;21:92-95. doi: 10.1007/s00467-005-2051-1
23. Wiesen J, Adkins M, Fortune S, et al. Evaluation of pediatric patients with mild-to-moderate hypertension: yield of diagnostic testing. Pediatrics. 2008;122:e988-993. doi: 10.1542/peds.2008-0365
24. Kapur G, Ahmed M, Pan C, et al. Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report. J Clin Hypertens (Greenwich). 2010;12:34-39. doi: 10.1111/j.1751-7176.2009.00195.x
25. Anyaegbu EI, Dharnidharka VR. Hypertension in the teenager. Pediatr Clin North Am. 2014;61:131-151. doi: 10.1016/j.pcl.2013.09.011
26. Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medical setting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-653. doi: 10.1016/j.chc.2012.05.013
27. Farpour-Lambert NJ, Aggoun Y, Marchand LM, et al. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54:2396-2406. doi: 10.1016/j.jacc.2009.08.030
28. Li JS, Baker-Smith CM, Smith PB, et al. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis. Clin Pharmacol Ther. 2008;84:315-319. doi: 10.1038/clpt.2008.113
29. Singer PS. Updates on hypertension and new guidelines. Adv Pediatr. 2019;66:177-187. doi: 10.1016/j.yapd.2019.03.009
30. Torrance B, McGuire KA, Lewanczuk R, et al. Overweight, physical activity and high blood pressure in children: a review of the literature. Vasc Health Risk Manag. 2007;3:139-149.
31. DASH eating plan. National Heart, Lung, and Blood Institute. Accessed April 26, 2021. www.nhlbi.nih.gov/health-topics/dash-eating-plan
32. Nutritional goals for age-sex groups based on dietary reference intakes and dietary guidelines recommendations (Appendix 7). In: US Department of Agriculture. Dietary guidelines for Americans, 2015-2020. 8th ed. December 2015;97-98. Accessed April 26, 2021. https://health.gov/sites/default/files/2019-09/2015-2020_Dietary_Guidelines.pdf
33. Asghari G, Yuzbashian E, Mirmiran P, et al. Dietary Approaches to Stop Hypertension (DASH) dietary pattern is associated with reduced incidence of metabolic syndrome in children and adolescents. J Pediatr. 2016;174:178-184.e1. doi: 10.1016/j.jpeds.2016.03.077
34. Damasceno MMC, de Araújo MFM, de Freitas RWJF, et al. The association between blood pressure in adolescents and the consumption of fruits, vegetables and fruit juice–an exploratory study. J Clin Nurs. 2011;20:1553-1560. doi: 10.1111/j.1365-2702.2010.03608.x
35. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N Am. 2018;27:63-76. doi: 10.1016/j.chc.2017.08.003
36. Kumar S, King EC, Christison, et al; POWER Work Group. Health outcomes of youth in clinical pediatric weight management programs in POWER. J Pediatr. 2019;208:57-65.e4. doi: 10.1016/j.jpeds.2018.12.049
37. Gregoski MJ, Barnes VA, Tingen MS, et al. Breathing awareness meditation and LifeSkills® Training programs influence upon ambulatory blood pressure and sodium excretion among African American adolescents. J Adolesc Health. 2011;48:59-64. doi: 10.1016/j.jadohealth.2010.05.019
38. Escape Trial Group; E, Trivelli A, Picca S, et al. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361:1639-1650. doi: 10.1056/NEJMoa0902066
PRACTICE RECOMMENDATIONS
› Measure the blood pressure (BP) of all children 3 years and older annually; those who have a specific comorbid condition (eg, obesity, diabetes, renal disease, or an aortic-arch abnormality) or who are taking medication known to elevate BP should have their BP checked at every health care visit. C
› Encourage lifestyle modification as the initial treatment for elevated BP or hypertension in children. A
› Utilize pharmacotherapy for (1) children with stage 1 hypertension who have failed to meet BP goals after 3 to 6 months of lifestyle modification and (2) children with stage 2 hypertension who do not have a modifiable risk factor, such as obesity. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
