Cardiology

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

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

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

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

Individuals who have hypertension at any age are more likely to experience more rapid cognitive decline compared with their counterparts with normal blood pressure, new research shows. In a retrospective study of more than 15,000 participants, hypertension during middle age was associated with memory decline, and onset at later ages was linked to worsening memory and global cognition.

The investigators found that prehypertension, defined as systolic pressure of 120-139 mm Hg or diastolic pressure of 80-89 mm Hg, was also linked to accelerated cognitive decline.

Although duration of hypertension was not associated with any marker of cognitive decline, blood pressure control “can substantially reduce hypertension’s deleterious effect on the pace of cognitive decline,” said study investigator Sandhi M. Barreto, MD, PhD, professor of medicine at Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

The findings were published online Dec. 14 in Hypertension.
 

Unanswered questions

Hypertension is an established and highly prevalent risk factor for cognitive decline, but the age at which it begins to affect cognition is unclear. Previous research suggests that onset during middle age is associated with more harmful cognitive effects than onset in later life. One reason for this apparent difference may be that the duration of hypertension influences the magnitude of cognitive decline, the researchers noted.

Other studies have shown that prehypertension is associated with damage to certain organs, but its effects on cognition are uncertain. In addition, the effect of good blood pressure control with antihypertensive medications and the impact on cognition are also unclear.

To investigate, the researchers examined data from the ongoing, multicenter ELSA-Brasil study. ELSA-Brasil follows 15,105 civil servants between the ages of 35 and 74 years. Dr. Barreto and team assessed data from visit 1, which was conducted between 2008 and 2010, and visit 2, which was conducted between 2012 and 2014.

At each visit, participants underwent a memory test, a verbal fluency test, and the Trail Making Test Part B. The investigators calculated Z scores for these tests to derive a global cognitive score.

Blood pressure was measured on the right arm, and hypertension status, age at the time of hypertension diagnosis, duration of hypertension diagnosis, hypertension treatment, and control status were recorded. Other covariables included sex, education, race, smoking status, physical activity, body mass index, and total cholesterol level.

The researchers excluded patients who did not undergo cognitive testing at visit 2, those who had a history of stroke at baseline, and those who initiated antihypertensive medications despite having normotension. After exclusions, the analysis included 7,063 participants (approximately 55% were women, 15% were Black).

At visit 1, the mean age of the group was 58.9 years, and 53.4% of participants had 14 or more years of education. In addition, 22% had prehypertension, and 46.8% had hypertension. The median duration of hypertension was 7 years; 29.8% of participants with hypertension were diagnosed with the condition during middle age.

Of those who reported having hypertension at visit 1, 7.3% were not taking any antihypertensive medication. Among participants with hypertension who were taking antihypertensives, 31.2% had uncontrolled blood pressure.
 

Independent predictor

Results showed that prehypertension independently predicted a significantly greater decline in verbal fluency (Z score, –0.0095; P < .01) and global cognitive score (Z score, –0.0049; P < .05) compared with normal blood pressure.

At middle age, hypertension was associated with a steeper decline in memory (Z score, –0.0072; P < .05) compared with normal blood pressure. At older ages, hypertension was linked to a steeper decline in both memory (Z score, –0.0151; P < .001) and global cognitive score (Z score, –0.0080; P < .01). Duration of hypertension, however, did not significantly predict changes in cognition (P < .109).

Among those with hypertension who were taking antihypertensive medications, those with uncontrolled blood pressure experienced greater declines in rapid memory (Z score, –0.0126; P < .01) and global cognitive score (Z score, –0.0074; P < .01) than did those with controlled blood pressure.

The investigators noted that the study participants had a comparatively high level of education, which has been shown to “boost cognitive reserve and lessen the speed of age-related cognitive decline,” Dr. Barreto said. However, “our results indicate that the effect of hypertension on cognitive decline affects individuals of all educational levels similarly,” she said.

Dr. Barreto noted that the findings have two major clinical implications. First, “maintaining blood pressure below prehypertension levels is important to preserve cognitive function or delay cognitive decline,” she said. Secondly, “in hypertensive individuals, keeping blood pressure under control is essential to reduce the speed of cognitive decline.”

The researchers plan to conduct further analyses of the data to clarify the observed relationship between memory and verbal fluency. They also plan to examine how hypertension affects long-term executive function.
 

‘Continuum of risk’

Commenting on the study, Philip B. Gorelick, MD, MPH, adjunct professor of neurology (stroke and neurocritical care) at Northwestern University, Chicago, noted that, so far, research suggests that the risk for stroke associated with blood pressure levels should be understood as representing a continuum rather than as being associated with several discrete points.

“The same may hold true for cognitive decline and dementia. There may be a continuum of risk whereby persons even at so-called elevated but relatively lower levels of blood pressure based on a continuous scale are at risk,” said Dr. Gorelick, who was not involved with the current study.

The investigators relied on a large and well-studied population of civil servants. However, the population’s relative youth and high level of education may limit the generalizability of the findings, he noted. In addition, the follow-up time was relatively short.

“The hard endpoint of dementia was not studied but would be of interest to enhance our understanding of the influence of blood pressure elevation on cognitive decline or dementia during a longer follow-up of the cohort,” Dr. Gorelick said.

The findings also suggest the need to better understand mechanisms that link blood pressure elevation with cognitive decline, he added.

They indicate “the need for additional clinical trials to better elucidate blood pressure lowering targets for cognitive preservation in different groups of persons at risk,” such as those with normal cognition, those with mild cognitive impairment, and those with dementia, said Dr. Gorelick. “For example, is it safe and efficacious to lower blood pressure in persons with more advanced cognitive impairment or dementia?” he asked.

The study was funded by the Brazilian Coordination for the Improvement of Higher Education Personnel. Dr. Barreto has received support from the Research Agency of the State of Minas Gerais. Although Dr. Gorelick was not involved in the ELSA-Brasil cohort study, he serves on a data monitoring committee for a trial of a blood pressure–lowering agent in the preservation of cognition.

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

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

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

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

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

Although guidelines generally recommend ambulatory over home blood pressure monitoring for diagnosing hypertension, new research questions home BP monitoring’s role as second fiddle.

One week of home BP monitoring (HBPM) was more reliable than one 24-hour ambulatory BP or nine mercury readings across three office visits among younger, untreated participants in the Improving the Detection of Hypertension study.

The reliability coefficients were 0.938, 0.846, and 0.894 for systolic BP and 0.918, 0.843, and 0.847 for diastolic BP, respectively.

Further, HBPM had the strongest association with left ventricular mass index (LVMI), a predictor of adverse cardiovascular events, according to researchers led by Joseph E. Schwartz, PhD, Stony Brook (N.Y.) University and Columbia University Irving Medical Center, New York.

The association with LVMI also remained after multivariate adjustment and after correcting for regression dilution bias, indicating the results were not a result of differences in the number of readings, they write in the study, published online in the Journal of the American College of Cardiology.

Whenever patients have an elevated blood pressure for the first time or even borderline elevated BP, guidelines recommend clinicians request a 24-hour ambulatory recording or home monitoring, Dr. Schwartz said in an interview. “I think this has the potential, for that purpose, to put ambulatory blood pressure monitoring out of business, even though that’s what I’ve done for 30 years.”

Previous studies have shown that home and ambulatory BP monitoring (ABPM) correlate more strongly with target-organ damage and cardiovascular outcomes than office BP, but head-to-head outcomes trials of the two techniques are lacking. A recent systematic review also found scant evidence supporting one approach over the other for predicting cardiovascular events or mortality.

An accompanying editorial notes that ABPM is largely unavailable to primary care physicians in the United States and poorly reimbursed. “Thus the demonstration that HBPM is more reliable and associates more closely with LVMI than ABPM, if confirmed, would carry the potential to change clinical practice,” wrote Robert M. Carey, MD, University of Virginia Health System in Charlottesville, and Thomas H. Marwick, MBBS, PhD, MPH, Baker Heart and Diabetes Institute, Melbourne.

In a comment, ABPM proponent Raymond R. Townsend, MD, said, “Honestly, it may be that we’ll need to act on this. I’m not quite ready to do that and change my practice patterns but, on the other hand, I can’t sweep this under the rug.”

He noted that it’s ironic the study is coauthored by the late Thomas Pickering, MD, a maven of ABPM who coined the term “white-coat hypertension” and pointed out masked hypertension.

That said, “it raised the bar on ambulatory blood pressure monitoring: Is it really worth our public health dollars? So I think it’s a very good call to arms,” said Dr. Townsend, who directs the hypertension program at the University of Pennsylvania, Philadelphia.

Ambulatory BP monitoring has long been considered the preferred method but, from a cost standpoint, HBPM is more attractive because the devices can be used more than once and track more than one person in a household, he said. The Center for Medicare Management also has a code in the 2020 bundle to reimburse physicians $15 for training patients and has a monthly charge for communicating with those filing regularly. “You’re not going to get rich doing monitoring of home BP, but at least the government is recognizing we are moving more and more to the home base in terms of our managing common conditions like blood pressure.”

One of the attractions of ABPM is the ability to do every half hour to every hour nocturnal pressures, but at least one home monitor, manufactured by Microlife, has added a nocturnal feature, Dr. Townsend noted. “So that’s just one more incoming against the ABPM defenses about why ABPMs are still better.”

The study enrolled a community-based sample of 408 participants who had office BP assessed at three visits (three readings per visit) using a mercury sphygmomanometer, a BpTRU (VSM MedTech) automated oscillometric device, and a home-validated Omron Healthcare oscillometric device.

After 5 minutes of in-office training and receipt of a reference sheet, participants also completed 3 weeks of HBPM with the Omron device as well as two 24-hour ambulatory measurements (Spacelabs Healthcare, Model 90207). Cardiovascular evaluations, including two-dimensional echocardiograms, were performed during the fifth office visit.

The 400 participants who completed all five visits had a mean age of 41 years, mean LVMI of 79.3 g/m², and mean office systolic BP ranging from 116.0 to 117.2 mm Hg and diastolic BP from 75.6 to 76.5 mm Hg.

Both before and after correction for regression dilution bias, home systolic and diastolic BP were more highly correlated with LVMI than 24-hour ambulatory or office mercury readings. The corrected correlations for systolic BP were 0.501, 0.430, and 0.389, respectively.

After multivariable adjustment including office and 24-hour ambulatory BP, 10 mm Hg higher systolic and diastolic home BP were associated with 5.07 g/m² (P = .001) and 3.92 g/m² (P = .07) higher LVMI, respectively. After adjustment for home BP, however, neither systolic or diastolic office BP nor ambulatory BP was associated with LVMI.

Dr. Townsend and editorialists Dr. Carey and Dr. Marwick pointed out the study included a younger population in whom just 30% to 50% would have been classified as having hypertension by the 2017 American College of Cardiology/American Heart Association guidelines, which Dr. Carey helped to pen.

“These people are young and older people have a different kind of blood pressure driven more by the stiffness in their circulation and less by the resistance to blood flow that you find more characteristic in younger people,” Dr. Townsend observed.

“I don’t know that you can extrapolate the findings from this study in healthy, younger untreated people to older, perhaps sicker, and more diabetic people where the real action is and where the endpoints like heart attack, death, and stroke actually occur,” he said.

The results suggest measurement of resting daytime BP may be relatively more important than dynamic daytime and/or nocturnal parameters in predicting subclinical cardiac target organ damage, but this requires further study, Dr. Carey and Dr. Marwick noted.

Commenting further, they wrote that the results suggest “HBPM could be especially important for detecting elevated BP and hypertension early in life, when adults are relatively healthy, but those with hypertension have a high lifetime risk of CVD.”

Dr. Schwartz acknowledged the study didn’t include the typical hypertensive patient but said it goes to the central question of whether the risk associated with blood pressure is because of the heart’s cumulative exposure over its lifetime and, thus, best measured with multiple readings taken under a variety of circumstances or with readings taken only at rest. 

“I’ve been posing that question at a conceptual level for 15 years, never in print, and this paper is the first hint, at least with respect to the left ventricular mass index … that getting a better measure of resting blood pressure is more important for controlling risk than the heart’s cumulative exposure to blood pressure, as measured by ambulatory,” he said.

The Improving the Detection of Hypertension study was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The authors disclosed no relevant financial relationships. Dr. Townsend reported receiving royalties as a writer for UpToDate and serving as an unpaid reviewer for ValidateBP.org. Dr. Carey is principal investigator and project director of a NIH R01 and P01 grant, respectively; vice chair of the 2017 ACC/AHA hypertension guideline writing committee; and chair of the AHA Resistant Hypertension Scientific Statement writing committee. Dr. Marwick disclosed no relevant financial relationships.

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

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

UPDATED DECEMBER 17

A panel of federal advisers on Tuesday effectively backed a bid to expand approval of sacubitril/valsartan for use in a form of heart failure for which there is not yet an approved medication.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The U.S. Food and Drug Administration asked its Cardiovascular and Renal Drugs Advisory Committee to broadly consider whether new analyses of data from the PARAGON-HF trial, combined with other information, could support use of sacubitril/valsartan (Entresto, Novartis) in heart failure with preserved ejection fraction (HFpEF).

The advisory committee voted 12-1 on this question, which can be seen as a marker for an expanded approval: “Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication?”

The dissenting vote was cast by the panel’s chairperson, Julia B. Lewis, MD, a professor of medicine from Vanderbilt University. In explaining her vote, Dr. Lewis cited concerns about expanding use of the drug, which has a potential for hypotension. But she noted that the rest of the panelists were “impressed by the totality of the evidence” presented, including a willingness to take a new look at the PARAGON-HF trial. This study was perceived at first pass as having failed to prove a benefit for people with HFpEF.

The 2019 initial unveiling of the PARAGON-HF results had dampened hopes for an evidence-based drug therapy for HFpEF. Patients treated with the first-of-its-kind renin-angiotensin system (RAS) inhibitor, compared with those who received standard valsartan, had 13% fewer heart failure hospitalizations or cardiovascular (CV) deaths over an average of about 3 years, but the difference missed significance at a P value of .059.

“Everybody agreed that the P value of .05 was not written in stone,” Dr. Lewis said in summarizing the panelists’ views on the voting question.

At the FDA’s request, the panel also addressed several other questions without voting on them. The agency asked the panel to describe the patient population for whom an expanded approval would be appropriate. The FDA initially approved sacubitril/valsartan in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Novartis in April submitted an application to the FDA, seeking to expand the use of sacubitril/valsartan from the currently approved indication for the treatment of chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) to include what the company terms “the adjacent population of patients with preserved ejection fraction (HFpEF) who have a left ventricular ejection fraction (LVEF) below normal.” The American Society of Echocardiography and European Association of Cardiovascular Imaging define normal LVEF and normal range (±2 standard deviations) as 62% (range, 52%-72%) in men and 64% (range, 54%-74%) in women, Novartis said in its briefing materials for the meeting.

FDA panelist Christopher M. O’Connor, MD, for example, suggested that an expanded approval could allow for use of sacubitril/valsartan for the reduction of heart failure or hospitalization in patients with mildly reduced ejection fraction as defined by greater than 45% through 55%. FDA panelist C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles, suggested extending this to 57% to acknowledge the higher threshold for women.

Another FDA panelist, Steven E. Nissen, MD, of the Cleveland Clinic, argued against use of imprecise terms in defining an expanded patient population for sacubitril/valsartan. If used in the right patient population, the drug could provide a benefit for people who have active heart failure with symptoms, including preventing hospitalizations and renal disease, he said.

“If you are symptomatic with a syndrome that’s consistent with heart failure and you have an ejection fraction below the lower limits of normal, I believe it’s in the public interest for you to get sacubitril/valsartan,” Dr. Nissen said.

The FDA usually follows the advice of its panels, but is not obligated to. But in this case, the agency staff were clearly seeking a path for an expanded approval of sacubitril/valsartan.


 

Challenging a standard

The FDA had encouraged Novartis to submit the supplementary application for the HFpEF indication and even suggested some of the post-hoc analyses, the agency staff said in a briefing document for the meeting.

PARAGON-HF illustrated some of the agency’s concerns about missed opportunities in general in large research trials. Some events of interest in studies may be miscounted due to a lack of information such as a requirement for the presence of physical examination findings that are not documented in the patient’s dossier, the FDA staff said.

“We would like to consider giving ‘partial credit’ to events based on the level of evidence provided, e.g., use of an ordinal variable rather than a dichotomous ‘yes’ or ‘no,’ ” the staff said in the briefing document.

At the panel meeting, Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, told the panelists there is no basis in law for setting a P value of .05 as the benchmark on whether to declare a trial a success or failure.

“I wanted to take a few minutes and make sure that you on the committee understands what flexibility you have in addressing the case study in question,” Dr. Stockbridge said at the start of the meeting.

He then reviewed cases where the FDA had approved claims for cardiac medicines that had not shown desired results in key tests. These include approval of enalapril for use in asymptomatic left ventricular dysfunction on the basis of the SOLVD-Prevention trial, approval of digoxin for heart failure on the basis of the DIG study, and approval of carvedilol for reduced ejection fraction following myocardial infarction on

the basis of the CAPRICORN study, Dr. Stockbridge said.

In reviewing the data for sacubitril/valsartan, FDA staff noted a similarity between investigator-reported and adjudicated results, Stockbridge said.

“This suggested that there were events that did not need all evidentiary criteria as qualified events, but likely were nonetheless,” he said. “This is an example of dichotomization of events being wasteful of information.”

Post-hoc exploratory analyses in PARAGON-HF were able to meet the commonly used standard, according to the FDA briefing document. Among the key findings of these analyses were:

• An analysis of investigator-reported events for the primary composite endpoint of total hospitalizations for heart failure (HHF) and cardiovascular (CV) death demonstrated a rate ratio (RR) of 0.84 (95% confidence interval 0.74- 0.97; P = .01).
• Investigator-reported events added 226 and 290 HHF events but decreased CV death by 56 and 58 events in the sacubitril/valsartan and valsartan arms, respectively. Hence, a net 170 and 232 events were added to the clinical endpoint committee–reported primary composite endpoint leading to a P value of .01, without a significant change in RR.
• Analysis of investigator-reported expanded primary composite endpoint events including total HHF, urgent HF visits, and CV death demonstrated a RR of 0.83 (95% CI, 0.73-0.95; P = .006. There were 136 and 173 investigator-reported urgent HF events in sacubitril/valsartan and valsartan arms, respectively.

Opening a floodgate?

Cynthia L. Chauhan, MSW, of Wichita, Kansas, who served as the consumer representative on the panel, questioned whether a decision to revisit the data on PARAGON-HF might lead drugmakers to seek to repurpose other failed trials.

“Are we opening any kind of floodgate for other researchers to go back and see this is an invitation to try to, for want of a better term, back-door their way into some approvals?” Ms. Chauhan asked.

Dr. Nissen assured her that this concern was valid and would be considered. The goal would be to allow some flexibility in cases that merit further consideration, while preventing companies from data mining until they find some evidence to support an FDA application, he said.

Re-analyzing trials “should be done carefully, conservatively, and only when it really is compelling that the public interest supports it,” Dr. Nissen stressed.

Panelists reported no conflicts of interest related to the topic of the meeting.
 

Middle-aged women with PTSD and comorbid depression have a nearly fourfold increased risk for early death from a variety of causes in comparison with their peers who do not have those conditions, new research shows.

“Women with more severe symptoms of depression and PTSD were more at risk, compared with those with fewer symptoms or women with symptoms of only PTSD or only depression,” lead investigator Andrea Roberts, PhD, Harvard School of Public Health, Boston, said in an interview.

Health care providers “should be aware that mental health is a critical component of overall health and is tightly entwined with physical health. Identifying and treating mental health issues should be a foundational part of general health practice,” said Dr. Roberts.

The study was published online Dec. 4 in JAMA Network Open.
 

Mental health fundamental to survival

The researchers studied more than 51,000 mostly White women from the Nurses Health Study II who were followed for 9 years (2008-2017). At baseline in 2008, the women were aged between 43 and 64 years (mean age, 53.3 years).

Women with high levels of PTSD (six or seven symptoms) and probable depression were nearly four times more likely to die during follow-up than their peers who did not have these conditions (hazard ratio, 3.8; 95% confidence interval, 2.65-5.45; P < .001).

With adjustment for health factors such as smoking and body mass index, women with a high level of PTSD and depression remained at increased risk for early death (HR, 3.11; 95% CI, 2.16-4.47; P < .001).

The risk for early death was also elevated among women with moderate PTSD (four or five symptoms) and depression (HR, 2.03; 95% CI, 1.35-3.03; P < .001) and women with subclinical PTSD and depression (HR, 2.85; 95% CI, 1.99-4.07; P < .001) compared with those who did not have PTSD or depression.

Among women with PTSD symptoms and depression, the incidence of death from nearly all major causes was increased, including death from cardiovascular disease, respiratory disease, type 2 diabetes, unintentional injury, suicide, and other causes.

“These findings provide further evidence that mental health is fundamental to physical health – and to our very survival. We ignore our emotional well-being at our peril,” senior author Karestan Koenen, PhD, said in a news release.
 

New knowledge

Commenting on the findings, Jennifer Sumner, PhD, said that it’s “critical to appreciate the physical health consequences of psychopathology in individuals who have experienced trauma. This study adds to a growing literature demonstrating that the impact extends far beyond emotional health.

“Furthermore, these results highlight the potential value of promoting healthy lifestyle changes in order to reduce the elevated mortality risk in trauma-exposed individuals with co-occurring PTSD and depression,” said Dr. Sumner, who is with the department of psychology, University of California, Los Angeles.

She noted that this study builds on other work that links PTSD to mortality in men.

“Most work on posttraumatic psychopathology and physical health has actually been conducted in predominantly male samples of veterans, so these findings in women exposed to a variety of traumatic experiences extend the literature in important ways,” said Dr. Sumner.

“It’s also important to note that PTSD and depression are more prevalent in women than in men, so demonstrating these associations in women is particularly relevant,” she added.

Funding for the study was provided by the National Institutes of Heath. The authors disclosed no relevant financial relationships. Dr. Sumner has collaborated with the study investigators on prior studies.

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

Middle-aged women with PTSD and comorbid depression have a nearly fourfold increased risk for early death from a variety of causes in comparison with their peers who do not have those conditions, new research shows.

“Women with more severe symptoms of depression and PTSD were more at risk, compared with those with fewer symptoms or women with symptoms of only PTSD or only depression,” lead investigator Andrea Roberts, PhD, Harvard School of Public Health, Boston, said in an interview.

Health care providers “should be aware that mental health is a critical component of overall health and is tightly entwined with physical health. Identifying and treating mental health issues should be a foundational part of general health practice,” said Dr. Roberts.

The study was published online Dec. 4 in JAMA Network Open.
 

Mental health fundamental to survival

The researchers studied more than 51,000 mostly White women from the Nurses Health Study II who were followed for 9 years (2008-2017). At baseline in 2008, the women were aged between 43 and 64 years (mean age, 53.3 years).

Women with high levels of PTSD (six or seven symptoms) and probable depression were nearly four times more likely to die during follow-up than their peers who did not have these conditions (hazard ratio, 3.8; 95% confidence interval, 2.65-5.45; P < .001).

With adjustment for health factors such as smoking and body mass index, women with a high level of PTSD and depression remained at increased risk for early death (HR, 3.11; 95% CI, 2.16-4.47; P < .001).

The risk for early death was also elevated among women with moderate PTSD (four or five symptoms) and depression (HR, 2.03; 95% CI, 1.35-3.03; P < .001) and women with subclinical PTSD and depression (HR, 2.85; 95% CI, 1.99-4.07; P < .001) compared with those who did not have PTSD or depression.

Among women with PTSD symptoms and depression, the incidence of death from nearly all major causes was increased, including death from cardiovascular disease, respiratory disease, type 2 diabetes, unintentional injury, suicide, and other causes.

“These findings provide further evidence that mental health is fundamental to physical health – and to our very survival. We ignore our emotional well-being at our peril,” senior author Karestan Koenen, PhD, said in a news release.
 

New knowledge

Commenting on the findings, Jennifer Sumner, PhD, said that it’s “critical to appreciate the physical health consequences of psychopathology in individuals who have experienced trauma. This study adds to a growing literature demonstrating that the impact extends far beyond emotional health.

“Furthermore, these results highlight the potential value of promoting healthy lifestyle changes in order to reduce the elevated mortality risk in trauma-exposed individuals with co-occurring PTSD and depression,” said Dr. Sumner, who is with the department of psychology, University of California, Los Angeles.

She noted that this study builds on other work that links PTSD to mortality in men.

“Most work on posttraumatic psychopathology and physical health has actually been conducted in predominantly male samples of veterans, so these findings in women exposed to a variety of traumatic experiences extend the literature in important ways,” said Dr. Sumner.

“It’s also important to note that PTSD and depression are more prevalent in women than in men, so demonstrating these associations in women is particularly relevant,” she added.

Funding for the study was provided by the National Institutes of Heath. The authors disclosed no relevant financial relationships. Dr. Sumner has collaborated with the study investigators on prior studies.

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

Middle-aged women with PTSD and comorbid depression have a nearly fourfold increased risk for early death from a variety of causes in comparison with their peers who do not have those conditions, new research shows.

“Women with more severe symptoms of depression and PTSD were more at risk, compared with those with fewer symptoms or women with symptoms of only PTSD or only depression,” lead investigator Andrea Roberts, PhD, Harvard School of Public Health, Boston, said in an interview.

Health care providers “should be aware that mental health is a critical component of overall health and is tightly entwined with physical health. Identifying and treating mental health issues should be a foundational part of general health practice,” said Dr. Roberts.

The study was published online Dec. 4 in JAMA Network Open.
 

Mental health fundamental to survival

The researchers studied more than 51,000 mostly White women from the Nurses Health Study II who were followed for 9 years (2008-2017). At baseline in 2008, the women were aged between 43 and 64 years (mean age, 53.3 years).

Women with high levels of PTSD (six or seven symptoms) and probable depression were nearly four times more likely to die during follow-up than their peers who did not have these conditions (hazard ratio, 3.8; 95% confidence interval, 2.65-5.45; P < .001).

With adjustment for health factors such as smoking and body mass index, women with a high level of PTSD and depression remained at increased risk for early death (HR, 3.11; 95% CI, 2.16-4.47; P < .001).

The risk for early death was also elevated among women with moderate PTSD (four or five symptoms) and depression (HR, 2.03; 95% CI, 1.35-3.03; P < .001) and women with subclinical PTSD and depression (HR, 2.85; 95% CI, 1.99-4.07; P < .001) compared with those who did not have PTSD or depression.

Among women with PTSD symptoms and depression, the incidence of death from nearly all major causes was increased, including death from cardiovascular disease, respiratory disease, type 2 diabetes, unintentional injury, suicide, and other causes.

“These findings provide further evidence that mental health is fundamental to physical health – and to our very survival. We ignore our emotional well-being at our peril,” senior author Karestan Koenen, PhD, said in a news release.
 

New knowledge

Commenting on the findings, Jennifer Sumner, PhD, said that it’s “critical to appreciate the physical health consequences of psychopathology in individuals who have experienced trauma. This study adds to a growing literature demonstrating that the impact extends far beyond emotional health.

“Furthermore, these results highlight the potential value of promoting healthy lifestyle changes in order to reduce the elevated mortality risk in trauma-exposed individuals with co-occurring PTSD and depression,” said Dr. Sumner, who is with the department of psychology, University of California, Los Angeles.

She noted that this study builds on other work that links PTSD to mortality in men.

“Most work on posttraumatic psychopathology and physical health has actually been conducted in predominantly male samples of veterans, so these findings in women exposed to a variety of traumatic experiences extend the literature in important ways,” said Dr. Sumner.

“It’s also important to note that PTSD and depression are more prevalent in women than in men, so demonstrating these associations in women is particularly relevant,” she added.

Funding for the study was provided by the National Institutes of Heath. The authors disclosed no relevant financial relationships. Dr. Sumner has collaborated with the study investigators on prior studies.

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

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

For 2021, the American Diabetes Association offers new guidance on assessing patients’ financial and social barriers to care, especially given the COVID-19 pandemic, individualizing treatment of patients with type 2 diabetes, and use of diabetes technology.

As it does every year, the annual update incorporates new clinical information that has become available since the last guideline, with occasional revisions during the year as needed. “Standards of Medical Care in Diabetes – 2021,” was published online as a supplement to Diabetes Care.

The new standards advise that patients be assessed for food and housing insecurity, social support, and “cost-related medication nonadherence,” and those found to have difficulty referred to appropriate community resources.

“Clinicians need to be sensitive to the fact that patients may have very good reasons for not taking their medication, [as in] if they can’t afford it,” ADA chief science & medical officer Robert A. Gabbay, MD, PhD, said in an interview.

Dr. Gabbay noted that “a heightened awareness” of social determinants of health is weaved throughout the 2021 standards because of the pandemic, with information on the topic derived from a July 2020 joint consensus statement in Diabetes Care, endorsed by a number of other societies, as well as a November publication also in Diabetes Care.

“We made several recommendations that speak to social determinants of health, placing an emphasis on engaging in conversations around this subject and screening for related issues such as food insecurity that weren’t there previously,” he said.

“Screening tools are suggested. It helped us to have an in-depth scientific review of the literature to know the prevalence of this in people with diabetes. ... Having the science to put it in was a key step,” Dr. Gabbay noted.
 

Consider kidney, heart disease in type 2 treatment individualization

Recent data from trials such as CREDENCE and DAPA-HF, among others, have been added to inform the choice of pharmacologic treatment in patients with type 2 diabetes with comorbid diabetic kidney disease and chronic heart failure.

“ADA has been advocating individualization of treatment based on comorbidities for a while, but we’ve taken more steps in that direction. Beyond lifestyle for all individuals with type 2 diabetes, clinicians want to think early on about which comorbidities patients have and then think about the appropriate treatment based on that,” Dr. Gabbay said.

And for the third year in a row, the section on cardiovascular disease and risk management has been endorsed by the American College of Cardiology.

“All the things in that section are very much aligned with ACC and that’s been a great partnership,” Dr. Gabbay said.

Now, ADA is in discussions with other professional societies representing relevant specialties to create further such unified messages.

“What we all want to avoid is having multiple different guidelines. We want to speak with one voice and find common ground as much as possible. … It makes it much easier for clinicians to know what to do. That’s the goal of all this,” he noted.
 

Diabetes technology: The rise of CGM during pandemic and beyond

New information about continuous glucose monitoring (CGM) has been added to the diabetes technology section. Use of CGM is now recommended for anyone with diabetes who takes multiple daily injections or uses an insulin pump, regardless of age or diabetes type. The document provides expanded advice on use of time in range data for glycemic monitoring, particularly during the COVID-19 pandemic when remote monitoring is preferable.

Insurers are increasingly covering CGM for patients on insulin, but it’s far from universal. While the ultimate goal is to ensure access to CGM for everyone with diabetes, those treated with multiple daily insulin doses are the priority for now.

“Our hope is that as there’s greater evidence there will be more movement towards coverage. There are still so many people for whom it’s quite clear they would benefit because they’re on insulin but don’t have access to it. That’s an important area that ADA is advocating for, and it’s reflected in the standards of care,” Dr. Gabbay said.

In another technology-related revision, the term “blinded” CGM has been replaced with “professional CGM,” because clinic-based use of the devices can be “blinded” to the patient or monitored in real-time by both the patient and clinician. Also, a new recommendation has been added to address skin reactions associated with diabetes technology use.

Information about use of CGM in hospital settings during the COVID-19 pandemic has also been added in the technology section.

The COVID-19 pandemic comes up again in the section on vaccines.

“We mention that people with diabetes should be considered high priority [for COVID-19 vaccines], and that’s something that ADA is strongly advocating for because 40% of COVID-19 deaths have been in people with diabetes,” Dr. Gabbay said.

Dr. Gabbay reported being on the advisory boards of Onduo, Health Reveal, Vida Health, Lark, and Form Health.

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

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The beneficial effects of sacubitril/valsartan on reverse cardiac remodeling in patients with heart failure and reduced ejection fraction have been well established, but those benefits haven’t been as clearly demonstrated to carry over to HFrEF patients who also have type 2 diabetes mellitus (T2DM).

Now, a post-hoc analysis of a pivotal clinical trial reports that those benefits do extend to patients with HFrEF and T2DM.

“It’s really not about a Sophie’s choice of whether you give this or that drug in these patients,” said corresponding author Javed Butler, MD, MPH, MBA. “We really ought to be giving all of these drugs – the angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose transporter 2 (SGLT-2) inhibitors – to our patients for the best outcomes.”

The post-hoc analysis, published in JACC: Heart Failure, evaluated 361 patients with T2DM who were enrolled in the PROVE-HF trial of sac/val therapy for HF, published in JAMA.

PROVE-HF evaluated biomarkers, myocardial remodeling, and outcomes through a year of treatment with sac/val. The primary endpoint was the level of changes in natriuretic peptide (NT-proBNP) concentrations, left-ventricle ejection fraction (LVEF) and overall Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores through 12 months of treatment.

The post hoc study reported that baseline NT-proBNP concentrations were higher in the DM patients (854 pg/mL vs. 706 pg/mL), but at 12 months those levels were 513 and 441 pg/mL, respectively.

LVEF changed similarly from baseline to 12 months in both groups: from 28.3% to 37% in the DM patients and from 28.1% to 38.34% in non-DM patients. Overall KCCQ-23 scores improved similarly in both groups, but longitudinal analyses found modestly higher gains in the T2DM group, 9.3 vs. 8.6 points (P = .07).

“The real reason I wanted to do this study is that I’m a huge fan of all the SGLT-2 inhibitors, and I’m very involved in those trials, and there is right now so much momentum behind SGLT-2 inhibitors that I don’t want people to forget that ARNI is still the base therapy for HF,” said Dr. Butler, chair of cardiovascular research and the department of medicine at the University of Mississippi in Jackson.

He noted that the size of the diabetes cohort in PROVE-HF “is a nonissue” for evaluating power of the post hoc analysis because it tracked key measures in the study population continuously at eight intervals over the 12 months.

The analysis further demonstrates the synergistic effects of ARNI and SGLT-2 inhibitors in patients with T2DM and HF that were also reported in the PARADIGM-HF study, Dr. Butler said.

“We have sort of moved on, saying that SGLT-2 inhibitors have a benefit on the heart, but the reverse is also true: ARNIs are still heart failure drugs, and we don’t think of them as diabetes drugs, but the PARADIGM-HF data showed that there was a substantial reduction in hemoglobin A1c in those who had diabetes,” he said.

The researchers noted that an absence of a control group may contribute to an overestimation of reverse cardiac remodeling in the T2DM patients, and that the PROVE-HF study wasn’t prospectively powered to delineate differences in how sac/val therapy affected patients with or without diabetes. “Future investigations seeking to evaluate differences by T2DM status after sacubitril/valsartan initiation may use our findings to plan prospective sample sizes,” the researchers wrote.

Dr. Butler disclosed financial relationships with Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide and Vifor. Lead author Muhammad Shahzeb Khan, MD, MSc, a professor at the University of Mississippi, has no relevant financial relationships to disclose.

SOURCE: Kahn MS et al. JACC: HF. 2020 Dec 9. doi: 10.1016/j.jchf.2020.09.014.
 

The American College of Cardiology and American Heart Association Task Force on Performance Measures have made two changes to performance measures for adults with atrial fibrillation or atrial flutter.

The 2020 Update to the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults With Atrial Fibrillation or Atrial Flutter was published online Dec. 7 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes. It was developed in collaboration with the Heart Rhythm Society.

Both performance measure changes were prompted by, and are in accordance with, the 2019 ACC/AHA/Heart Rhythm Society atrial fibrillation guideline focused update issued in January 2019, and reported by this news organization at that time.

The first change is the clarification that valvular atrial fibrillation is atrial fibrillation with either moderate or severe mitral stenosis or a mechanical heart valve. This change is incorporated into all the performance measures.

The second change, which only applies to the performance measure of anticoagulation prescribed, is the separation of a male and female threshold for the CHA₂DS₂-VASc score.

This threshold is now a score higher than 1 for men and higher than 2 for women, further demonstrating that the risk for stroke differs for men and women with atrial fibrillation or atrial flutter, the ACC/AHA noted in a press release.

“Successful implementation of these updated performance measures by clinicians and healthcare organizations will lead to quality improvement for adult patients with atrial fibrillation or atrial flutter,” they said.

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

The American College of Cardiology and American Heart Association Task Force on Performance Measures have made two changes to performance measures for adults with atrial fibrillation or atrial flutter.

The 2020 Update to the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults With Atrial Fibrillation or Atrial Flutter was published online Dec. 7 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes. It was developed in collaboration with the Heart Rhythm Society.

Both performance measure changes were prompted by, and are in accordance with, the 2019 ACC/AHA/Heart Rhythm Society atrial fibrillation guideline focused update issued in January 2019, and reported by this news organization at that time.

The first change is the clarification that valvular atrial fibrillation is atrial fibrillation with either moderate or severe mitral stenosis or a mechanical heart valve. This change is incorporated into all the performance measures.

The second change, which only applies to the performance measure of anticoagulation prescribed, is the separation of a male and female threshold for the CHA₂DS₂-VASc score.

This threshold is now a score higher than 1 for men and higher than 2 for women, further demonstrating that the risk for stroke differs for men and women with atrial fibrillation or atrial flutter, the ACC/AHA noted in a press release.

“Successful implementation of these updated performance measures by clinicians and healthcare organizations will lead to quality improvement for adult patients with atrial fibrillation or atrial flutter,” they said.

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

The American College of Cardiology and American Heart Association Task Force on Performance Measures have made two changes to performance measures for adults with atrial fibrillation or atrial flutter.

The 2020 Update to the 2016 ACC/AHA Clinical Performance and Quality Measures for Adults With Atrial Fibrillation or Atrial Flutter was published online Dec. 7 in the Journal of the American College of Cardiology and Circulation: Cardiovascular Quality and Outcomes. It was developed in collaboration with the Heart Rhythm Society.

Both performance measure changes were prompted by, and are in accordance with, the 2019 ACC/AHA/Heart Rhythm Society atrial fibrillation guideline focused update issued in January 2019, and reported by this news organization at that time.

The first change is the clarification that valvular atrial fibrillation is atrial fibrillation with either moderate or severe mitral stenosis or a mechanical heart valve. This change is incorporated into all the performance measures.

The second change, which only applies to the performance measure of anticoagulation prescribed, is the separation of a male and female threshold for the CHA₂DS₂-VASc score.

This threshold is now a score higher than 1 for men and higher than 2 for women, further demonstrating that the risk for stroke differs for men and women with atrial fibrillation or atrial flutter, the ACC/AHA noted in a press release.

“Successful implementation of these updated performance measures by clinicians and healthcare organizations will lead to quality improvement for adult patients with atrial fibrillation or atrial flutter,” they said.

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

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; dustinksmith@yahoo.com

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; dustinksmith@yahoo.com

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; dustinksmith@yahoo.com

ILLUSTRATIVE CASE

A 63-year-old man with a medical history significant for myocardial infarction (MI) 5 years ago presents to you for an annual exam. His medications include a daily aspirin, ­angiotensin-converting enzyme inhibitor, beta-blocker, and a high-intensity statin for coronary artery disease (CAD). On his fasting lipid panel, his low-density lipoprotein (LDL) level is 70 mg/dL, but his triglycerides remain elevated at 200 mg/dL despite dietary changes.

In addition to lifestyle modifications, what can be done to reduce his risk of another MI?

Patients with known cardiovascular disease (CVD) or multiple risk factors for CVD are at high risk of cardiovascular events, even when taking primary or secondary preventive medications such as statins.^2,3 In these patients, elevated triglycerides are an independent risk factor for increased rates of cardiovascular events.^4,5

The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of blood cholesterol recommend statin therapy for moderate (175-499 mg/dL) to severe (≥ 500 mg/dL) hypertriglyceridemia in appropriate patients with atherosclerotic CVD risk ≥ 7.5%, after appropriately addressing secondary causes of hypertriglycidemia.⁶

Previous studies have shown no benefit from combination therapy with triglyceride-lowering medications (eg, extended-release niacin and fibrates) and statins, compared with statin monotherapy.⁷ A recent meta-analysis concluded that omega-3 fatty acid supplements offer no reduction in cardiovascular morbidity or mortality, whether taken with or without statins.⁸

Interestingly, the randomized controlled Japan EPA Lipid Intervention Study (JELIS) demonstrated fewer major coronary events in patients with elevated cholesterol, with or without CAD, who took eicosapentaenoic acid (EPA)—a subtype of omega-3 fatty acids—plus a statin, compared with statin monotherapy.⁹

The REDUCE-IT trial evaluated icosapent ethyl, a highly purified EPA that has been shown to reduce triglycerides and, at the time this study was conducted, was approved for use solely for the reduction of triglyceride levels in adults with severe hypertriglyceridemia.^10,11

Continue to: Study Summary

STUDY SUMMARY

Patients with known CVD had fewercardiovascular events on icosapent ethyl

The multicenter, randomized controlled REDUCE-IT trial evaluated the effectiveness of icosapent ethyl, 2 g orally twice daily, on cardiovascular outcomes.¹ A total of 8179 patients, ≥ 45 years of age with hypertriglyceridemia and known CVD or ≥ 50 years with diabetes and at least 1 additional risk factor and no known CVD, were enrolled at 473 participating sites in 11 countries, including the United States.

Patients had a triglyceride level of 150 to 499 mg/dL and an LDL cholesterol level of 41 to 100 mg/dL, and were taking a stable dose of a statin for at least 4 weeks. The enrollment protocol was amended to increase the lower limit of triglycerides from 150 to 200 mg/dL about one-third of the way through the study. Among the study population, 70.7% of patients were enrolled for secondary prevention (ie, had established CVD) and 29.3% of patients were enrolled for primary prevention (ie, had diabetes and at least 1 additional risk factor but no known CVD). Exclusion criteria included severe heart failure, active severe liver disease, glycated hemoglobin > 10%, a planned surgical cardiac intervention, history of pancreatitis, or allergies to fish or shellfish products.

Outcomes. The primary end point was a composite outcome of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina.

Results. The median duration of follow-up was 4.9 years. From baseline to 1 year, the median change in triglycerides was an 18% reduction in the icosapent ethyl group but a 2% increase in the placebo group. Fewer patients in the icosapent ethyl group than the placebo group had a composite outcome event (17% vs 22%, respectively; hazard ratio [HR] = 0.75; 95% confidence interval [CI], 0.68-0.83; number needed to treat [NNT] to avoid 1 primary end point event = 21). Patients with known CVD had fewer composite outcome events in the icosapent ethyl group than the placebo group (19% vs 26%; HR = 0.73; 95% CI, 0.65-0.81; NNT = 14) but not in the primary prevention group vs the placebo group (12% vs 14%; HR = 0.88; 95% CI, 0.70-1.1).

In the entire population, all individual outcomes in the composite were significantly fewer in the icosapent ethyl group (cardiovascular death: HR = 0.8; 95% CI, 0.66-0.98; fatal or nonfatal MI: HR = 0.69; 95% CI, 0.58-0.81; revascularization: HR = 0.65; 95% CI, 0.55-0.78; unstable angina: HR = 0.68; 95% CI, 0.53-0.87; and fatal or nonfatal stroke: HR = 0.72; 95% CI, 0.55-0.93). All-cause mortality did not differ between groups (HR = 0.87; 95% CI, 0.74-1.02).

No significant differences in adverse events leading to discontinuation of the drug were reported between groups. Atrial fibrillation occurred more frequently in the icosapent ethyl group (5.3% vs 3.9%), but anemia (4.7% vs 5.8%) and gastrointestinal adverse events (33% vs 35%) were less common.

Continue to: What's New

WHAT’S NEW

First RCT to demonstrate valueof pairing icosapent ethyl with a statin

Many prior studies on use of omega-3 fatty acid supplements to treat hypertriglyceridemia did not show any benefit, possibly due to a low dose or low ratio of EPA in the study drug.⁸ One trial (JELIS) with favorable results was an open-label study, limited to patients in Japan. The REDUCE-IT study was the first randomized, placebo-controlled trial to show that icosapent ethyl treatment for hypertriglyceridemia in patients with known CVD who are taking a statin results in fewer cardiovascular events than statin use alone.

In this multinational trial of patients with hypertriglyceridemia and CVD or cardiovascular risk factors, icosapent ethyl significantly reduced the risk of cardiovascular events.

Also worth noting: Since publication of the REDUCE-IT study, the FDA has approved an expanded indication for icosapent ethyl for reduction of risk of cardiovascular events in statin-treated patients with hypertriglyceridemia and established CVD or diabetes and ≥ 2 additional cardiovascular risk factors.¹¹

CAVEATS

Drug’s benefit was not linkedto triglyceride level reductions

The cardiovascular benefits of icosapent ethyl were obtained irrespective of triglyceride levels achieved. This raises the question of other potential mechanisms of action of icosapent ethyl in achieving cardiovascular benefit. However, this should not preclude the use of icosapent ethyl for secondary prevention in appropriate patients.

CHALLENGES TO IMPLEMENTATION

Medication is pricey

Icosapent ethyl is an expensive medication, currently priced at an estimated $351/month using a nationally available discount pharmacy plan, although additional manufacturer’s discounts may apply.^12,13 The cost of the medication could be a consideration for widespread implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2020. The Family Physicians Inquiries Network. All rights reserved.

ILLUSTRATIVE CASE

A 63-year-old man with a medical history significant for myocardial infarction (MI) 5 years ago presents to you for an annual exam. His medications include a daily aspirin, ­angiotensin-converting enzyme inhibitor, beta-blocker, and a high-intensity statin for coronary artery disease (CAD). On his fasting lipid panel, his low-density lipoprotein (LDL) level is 70 mg/dL, but his triglycerides remain elevated at 200 mg/dL despite dietary changes.

In addition to lifestyle modifications, what can be done to reduce his risk of another MI?

Patients with known cardiovascular disease (CVD) or multiple risk factors for CVD are at high risk of cardiovascular events, even when taking primary or secondary preventive medications such as statins.^2,3 In these patients, elevated triglycerides are an independent risk factor for increased rates of cardiovascular events.^4,5

The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of blood cholesterol recommend statin therapy for moderate (175-499 mg/dL) to severe (≥ 500 mg/dL) hypertriglyceridemia in appropriate patients with atherosclerotic CVD risk ≥ 7.5%, after appropriately addressing secondary causes of hypertriglycidemia.⁶

Previous studies have shown no benefit from combination therapy with triglyceride-lowering medications (eg, extended-release niacin and fibrates) and statins, compared with statin monotherapy.⁷ A recent meta-analysis concluded that omega-3 fatty acid supplements offer no reduction in cardiovascular morbidity or mortality, whether taken with or without statins.⁸

Interestingly, the randomized controlled Japan EPA Lipid Intervention Study (JELIS) demonstrated fewer major coronary events in patients with elevated cholesterol, with or without CAD, who took eicosapentaenoic acid (EPA)—a subtype of omega-3 fatty acids—plus a statin, compared with statin monotherapy.⁹

The REDUCE-IT trial evaluated icosapent ethyl, a highly purified EPA that has been shown to reduce triglycerides and, at the time this study was conducted, was approved for use solely for the reduction of triglyceride levels in adults with severe hypertriglyceridemia.^10,11

Continue to: Study Summary

STUDY SUMMARY

Patients with known CVD had fewercardiovascular events on icosapent ethyl

The multicenter, randomized controlled REDUCE-IT trial evaluated the effectiveness of icosapent ethyl, 2 g orally twice daily, on cardiovascular outcomes.¹ A total of 8179 patients, ≥ 45 years of age with hypertriglyceridemia and known CVD or ≥ 50 years with diabetes and at least 1 additional risk factor and no known CVD, were enrolled at 473 participating sites in 11 countries, including the United States.

Patients had a triglyceride level of 150 to 499 mg/dL and an LDL cholesterol level of 41 to 100 mg/dL, and were taking a stable dose of a statin for at least 4 weeks. The enrollment protocol was amended to increase the lower limit of triglycerides from 150 to 200 mg/dL about one-third of the way through the study. Among the study population, 70.7% of patients were enrolled for secondary prevention (ie, had established CVD) and 29.3% of patients were enrolled for primary prevention (ie, had diabetes and at least 1 additional risk factor but no known CVD). Exclusion criteria included severe heart failure, active severe liver disease, glycated hemoglobin > 10%, a planned surgical cardiac intervention, history of pancreatitis, or allergies to fish or shellfish products.

Outcomes. The primary end point was a composite outcome of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina.

Results. The median duration of follow-up was 4.9 years. From baseline to 1 year, the median change in triglycerides was an 18% reduction in the icosapent ethyl group but a 2% increase in the placebo group. Fewer patients in the icosapent ethyl group than the placebo group had a composite outcome event (17% vs 22%, respectively; hazard ratio [HR] = 0.75; 95% confidence interval [CI], 0.68-0.83; number needed to treat [NNT] to avoid 1 primary end point event = 21). Patients with known CVD had fewer composite outcome events in the icosapent ethyl group than the placebo group (19% vs 26%; HR = 0.73; 95% CI, 0.65-0.81; NNT = 14) but not in the primary prevention group vs the placebo group (12% vs 14%; HR = 0.88; 95% CI, 0.70-1.1).

In the entire population, all individual outcomes in the composite were significantly fewer in the icosapent ethyl group (cardiovascular death: HR = 0.8; 95% CI, 0.66-0.98; fatal or nonfatal MI: HR = 0.69; 95% CI, 0.58-0.81; revascularization: HR = 0.65; 95% CI, 0.55-0.78; unstable angina: HR = 0.68; 95% CI, 0.53-0.87; and fatal or nonfatal stroke: HR = 0.72; 95% CI, 0.55-0.93). All-cause mortality did not differ between groups (HR = 0.87; 95% CI, 0.74-1.02).

No significant differences in adverse events leading to discontinuation of the drug were reported between groups. Atrial fibrillation occurred more frequently in the icosapent ethyl group (5.3% vs 3.9%), but anemia (4.7% vs 5.8%) and gastrointestinal adverse events (33% vs 35%) were less common.

Continue to: What's New

WHAT’S NEW

First RCT to demonstrate valueof pairing icosapent ethyl with a statin

Many prior studies on use of omega-3 fatty acid supplements to treat hypertriglyceridemia did not show any benefit, possibly due to a low dose or low ratio of EPA in the study drug.⁸ One trial (JELIS) with favorable results was an open-label study, limited to patients in Japan. The REDUCE-IT study was the first randomized, placebo-controlled trial to show that icosapent ethyl treatment for hypertriglyceridemia in patients with known CVD who are taking a statin results in fewer cardiovascular events than statin use alone.

In this multinational trial of patients with hypertriglyceridemia and CVD or cardiovascular risk factors, icosapent ethyl significantly reduced the risk of cardiovascular events.

Also worth noting: Since publication of the REDUCE-IT study, the FDA has approved an expanded indication for icosapent ethyl for reduction of risk of cardiovascular events in statin-treated patients with hypertriglyceridemia and established CVD or diabetes and ≥ 2 additional cardiovascular risk factors.¹¹

CAVEATS

Drug’s benefit was not linkedto triglyceride level reductions

The cardiovascular benefits of icosapent ethyl were obtained irrespective of triglyceride levels achieved. This raises the question of other potential mechanisms of action of icosapent ethyl in achieving cardiovascular benefit. However, this should not preclude the use of icosapent ethyl for secondary prevention in appropriate patients.

CHALLENGES TO IMPLEMENTATION

Medication is pricey

Icosapent ethyl is an expensive medication, currently priced at an estimated $351/month using a nationally available discount pharmacy plan, although additional manufacturer’s discounts may apply.^12,13 The cost of the medication could be a consideration for widespread implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2020. The Family Physicians Inquiries Network. All rights reserved.

ILLUSTRATIVE CASE

A 63-year-old man with a medical history significant for myocardial infarction (MI) 5 years ago presents to you for an annual exam. His medications include a daily aspirin, ­angiotensin-converting enzyme inhibitor, beta-blocker, and a high-intensity statin for coronary artery disease (CAD). On his fasting lipid panel, his low-density lipoprotein (LDL) level is 70 mg/dL, but his triglycerides remain elevated at 200 mg/dL despite dietary changes.

In addition to lifestyle modifications, what can be done to reduce his risk of another MI?

Patients with known cardiovascular disease (CVD) or multiple risk factors for CVD are at high risk of cardiovascular events, even when taking primary or secondary preventive medications such as statins.^2,3 In these patients, elevated triglycerides are an independent risk factor for increased rates of cardiovascular events.^4,5

The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of blood cholesterol recommend statin therapy for moderate (175-499 mg/dL) to severe (≥ 500 mg/dL) hypertriglyceridemia in appropriate patients with atherosclerotic CVD risk ≥ 7.5%, after appropriately addressing secondary causes of hypertriglycidemia.⁶

Previous studies have shown no benefit from combination therapy with triglyceride-lowering medications (eg, extended-release niacin and fibrates) and statins, compared with statin monotherapy.⁷ A recent meta-analysis concluded that omega-3 fatty acid supplements offer no reduction in cardiovascular morbidity or mortality, whether taken with or without statins.⁸

Interestingly, the randomized controlled Japan EPA Lipid Intervention Study (JELIS) demonstrated fewer major coronary events in patients with elevated cholesterol, with or without CAD, who took eicosapentaenoic acid (EPA)—a subtype of omega-3 fatty acids—plus a statin, compared with statin monotherapy.⁹

The REDUCE-IT trial evaluated icosapent ethyl, a highly purified EPA that has been shown to reduce triglycerides and, at the time this study was conducted, was approved for use solely for the reduction of triglyceride levels in adults with severe hypertriglyceridemia.^10,11

Continue to: Study Summary

STUDY SUMMARY

Patients with known CVD had fewercardiovascular events on icosapent ethyl

The multicenter, randomized controlled REDUCE-IT trial evaluated the effectiveness of icosapent ethyl, 2 g orally twice daily, on cardiovascular outcomes.¹ A total of 8179 patients, ≥ 45 years of age with hypertriglyceridemia and known CVD or ≥ 50 years with diabetes and at least 1 additional risk factor and no known CVD, were enrolled at 473 participating sites in 11 countries, including the United States.

Patients had a triglyceride level of 150 to 499 mg/dL and an LDL cholesterol level of 41 to 100 mg/dL, and were taking a stable dose of a statin for at least 4 weeks. The enrollment protocol was amended to increase the lower limit of triglycerides from 150 to 200 mg/dL about one-third of the way through the study. Among the study population, 70.7% of patients were enrolled for secondary prevention (ie, had established CVD) and 29.3% of patients were enrolled for primary prevention (ie, had diabetes and at least 1 additional risk factor but no known CVD). Exclusion criteria included severe heart failure, active severe liver disease, glycated hemoglobin > 10%, a planned surgical cardiac intervention, history of pancreatitis, or allergies to fish or shellfish products.

Outcomes. The primary end point was a composite outcome of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina.

Results. The median duration of follow-up was 4.9 years. From baseline to 1 year, the median change in triglycerides was an 18% reduction in the icosapent ethyl group but a 2% increase in the placebo group. Fewer patients in the icosapent ethyl group than the placebo group had a composite outcome event (17% vs 22%, respectively; hazard ratio [HR] = 0.75; 95% confidence interval [CI], 0.68-0.83; number needed to treat [NNT] to avoid 1 primary end point event = 21). Patients with known CVD had fewer composite outcome events in the icosapent ethyl group than the placebo group (19% vs 26%; HR = 0.73; 95% CI, 0.65-0.81; NNT = 14) but not in the primary prevention group vs the placebo group (12% vs 14%; HR = 0.88; 95% CI, 0.70-1.1).

In the entire population, all individual outcomes in the composite were significantly fewer in the icosapent ethyl group (cardiovascular death: HR = 0.8; 95% CI, 0.66-0.98; fatal or nonfatal MI: HR = 0.69; 95% CI, 0.58-0.81; revascularization: HR = 0.65; 95% CI, 0.55-0.78; unstable angina: HR = 0.68; 95% CI, 0.53-0.87; and fatal or nonfatal stroke: HR = 0.72; 95% CI, 0.55-0.93). All-cause mortality did not differ between groups (HR = 0.87; 95% CI, 0.74-1.02).

No significant differences in adverse events leading to discontinuation of the drug were reported between groups. Atrial fibrillation occurred more frequently in the icosapent ethyl group (5.3% vs 3.9%), but anemia (4.7% vs 5.8%) and gastrointestinal adverse events (33% vs 35%) were less common.

Continue to: What's New

WHAT’S NEW

First RCT to demonstrate valueof pairing icosapent ethyl with a statin

Many prior studies on use of omega-3 fatty acid supplements to treat hypertriglyceridemia did not show any benefit, possibly due to a low dose or low ratio of EPA in the study drug.⁸ One trial (JELIS) with favorable results was an open-label study, limited to patients in Japan. The REDUCE-IT study was the first randomized, placebo-controlled trial to show that icosapent ethyl treatment for hypertriglyceridemia in patients with known CVD who are taking a statin results in fewer cardiovascular events than statin use alone.

In this multinational trial of patients with hypertriglyceridemia and CVD or cardiovascular risk factors, icosapent ethyl significantly reduced the risk of cardiovascular events.

Also worth noting: Since publication of the REDUCE-IT study, the FDA has approved an expanded indication for icosapent ethyl for reduction of risk of cardiovascular events in statin-treated patients with hypertriglyceridemia and established CVD or diabetes and ≥ 2 additional cardiovascular risk factors.¹¹

CAVEATS

Drug’s benefit was not linkedto triglyceride level reductions

The cardiovascular benefits of icosapent ethyl were obtained irrespective of triglyceride levels achieved. This raises the question of other potential mechanisms of action of icosapent ethyl in achieving cardiovascular benefit. However, this should not preclude the use of icosapent ethyl for secondary prevention in appropriate patients.

CHALLENGES TO IMPLEMENTATION

Medication is pricey

Icosapent ethyl is an expensive medication, currently priced at an estimated $351/month using a nationally available discount pharmacy plan, although additional manufacturer’s discounts may apply.^12,13 The cost of the medication could be a consideration for widespread implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2020. The Family Physicians Inquiries Network. All rights reserved.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.