ILLUSTRATIVE CASE

A 27-year-old G1P000 at term with an uncomplicated pregnancy has been laboring for 6 hours with an epidural in place and a reassuring fetal heart tracing. She is at –2 station with complete cervical dilation and effacement. Should she push now or delay pushing to allow for more descent?

More than 10,000 women give birth each day in the United States, yet few of our approaches to labor management are evidence based.² For example, there are no clear guidelines on whether immediate pushing or delayed pushing (waiting 1-2 hours) in the second stage of labor (the time from complete cervical dilation to delivery of the fetus) leads to better outcomes.

A recent Cochrane review, which included very low- to moderate-quality trials of nulliparous and multiparous women using epidural analgesia showed that delayed pushing resulted in more vaginal deliveries, longer duration of second stage of labor, and shorter duration of pushing.³ But many of the trials included in this Cochrane review were noted to have study design limitations and significant heterogeneity.

A recent retrospective study found that delayed pushing resulted in longer duration of pushing and increased risks for cesarean section, operative vaginal delivery, and postpartum hemorrhage in nulliparous patients with and without epidurals.⁴ The World Health Organization recommends delayed pushing in women with epidural analgesia if time and fetal monitoring resources are available.⁵

STUDY SUMMARY

Does the timing of second stage pushing efforts affect outcomes?

This multicenter randomized controlled trial (RCT) evaluated the effect on spontaneous vaginal delivery of delayed pushing vs immediate pushing in 2404 term nulliparous women using epidural analgesia.¹ Patients were ≥ 37 weeks’ gestation. Once patients achieved 10 cm of cervical dilation, they were randomized in a 1:1 ratio to either immediate pushing or to delayed (for 60 minutes) pushing (unless there was an irresistible urge to push or they were otherwise instructed by their provider).

Outcome and results. The primary outcome was spontaneous vaginal delivery without the use of any operative support. The mean time to pushing after complete cervical dilation was 19 minutes in the immediate pushing group and 60 minutes in the delayed group. There was no difference in the rate of spontaneous vaginal delivery between the immediate and delayed pushing groups (86% vs 87%, respectively; P = .67). The immediate pushing group had a shorter duration of second stage of labor (102 minutes vs 134 minutes; mean difference [MD] = –32 minutes; 95% confidence interval [CI], –37 to –27; P < .001) and a slightly longer duration of active pushing (84 minutes vs 75 minutes; MD = 9.2 minutes; 95% CI, 6-13; P < .001).

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia.

There was no significant difference in operative vaginal or cesarean deliveries. Postpartum hemorrhage was lower in the immediate pushing group (2.3% vs 4%; risk ratio [RR] = 0.6; 95% CI, 0.3-0.9; P = .03; number needed to treat [NNT] = 58), as was chorioamnionitis (6.7% vs 9.1%; RR = 0.7; 95% CI, 0.66-0.90; P = .005; NNT = 40). There was no significant difference in neonatal morbidity between groups. And in subgroup analysis, there was no significant difference in rates of vaginal delivery based on fetal position (occiput anterior, posterior, or transverse) or station (defined as high [< 2 cm] or low [≥ 2 cm]) between groups. Recruitment was stopped early at 75% because there was no difference in the primary outcome and there was concern regarding an increased risk of hemorrhage in the delayed pushing group.

Continue to: WHAT'S NEW

WHAT’S NEW

There’s no good reason to delay pushing

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia, as it does not decrease the rate of spontaneous vaginal delivery. It does, however, increase the length of second stage labor and the risk of postpartum hemorrhage and chorioamnionitis.

CAVEATS

Study was stopped early, and groups were unblinded

This study was stopped early, so it is not known if it was underpowered for some of the secondary outcomes. Also, it was not possible to blind the groups, so it is not clear if any bias in patient management or diagnosis resulted.

CHALLENGES TO IMPLEMENTATION

Will current practice and culture pose obstacles?

Although the overt challenges to enacting a policy of immediate pushing are minimal, the inertia of current practice and culture could affect the implementation of this strategy.

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.

ILLUSTRATIVE CASE

A 27-year-old G1P000 at term with an uncomplicated pregnancy has been laboring for 6 hours with an epidural in place and a reassuring fetal heart tracing. She is at –2 station with complete cervical dilation and effacement. Should she push now or delay pushing to allow for more descent?

More than 10,000 women give birth each day in the United States, yet few of our approaches to labor management are evidence based.² For example, there are no clear guidelines on whether immediate pushing or delayed pushing (waiting 1-2 hours) in the second stage of labor (the time from complete cervical dilation to delivery of the fetus) leads to better outcomes.

A recent Cochrane review, which included very low- to moderate-quality trials of nulliparous and multiparous women using epidural analgesia showed that delayed pushing resulted in more vaginal deliveries, longer duration of second stage of labor, and shorter duration of pushing.³ But many of the trials included in this Cochrane review were noted to have study design limitations and significant heterogeneity.

A recent retrospective study found that delayed pushing resulted in longer duration of pushing and increased risks for cesarean section, operative vaginal delivery, and postpartum hemorrhage in nulliparous patients with and without epidurals.⁴ The World Health Organization recommends delayed pushing in women with epidural analgesia if time and fetal monitoring resources are available.⁵

STUDY SUMMARY

Does the timing of second stage pushing efforts affect outcomes?

This multicenter randomized controlled trial (RCT) evaluated the effect on spontaneous vaginal delivery of delayed pushing vs immediate pushing in 2404 term nulliparous women using epidural analgesia.¹ Patients were ≥ 37 weeks’ gestation. Once patients achieved 10 cm of cervical dilation, they were randomized in a 1:1 ratio to either immediate pushing or to delayed (for 60 minutes) pushing (unless there was an irresistible urge to push or they were otherwise instructed by their provider).

Outcome and results. The primary outcome was spontaneous vaginal delivery without the use of any operative support. The mean time to pushing after complete cervical dilation was 19 minutes in the immediate pushing group and 60 minutes in the delayed group. There was no difference in the rate of spontaneous vaginal delivery between the immediate and delayed pushing groups (86% vs 87%, respectively; P = .67). The immediate pushing group had a shorter duration of second stage of labor (102 minutes vs 134 minutes; mean difference [MD] = –32 minutes; 95% confidence interval [CI], –37 to –27; P < .001) and a slightly longer duration of active pushing (84 minutes vs 75 minutes; MD = 9.2 minutes; 95% CI, 6-13; P < .001).

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia.

There was no significant difference in operative vaginal or cesarean deliveries. Postpartum hemorrhage was lower in the immediate pushing group (2.3% vs 4%; risk ratio [RR] = 0.6; 95% CI, 0.3-0.9; P = .03; number needed to treat [NNT] = 58), as was chorioamnionitis (6.7% vs 9.1%; RR = 0.7; 95% CI, 0.66-0.90; P = .005; NNT = 40). There was no significant difference in neonatal morbidity between groups. And in subgroup analysis, there was no significant difference in rates of vaginal delivery based on fetal position (occiput anterior, posterior, or transverse) or station (defined as high [< 2 cm] or low [≥ 2 cm]) between groups. Recruitment was stopped early at 75% because there was no difference in the primary outcome and there was concern regarding an increased risk of hemorrhage in the delayed pushing group.

Continue to: WHAT'S NEW

WHAT’S NEW

There’s no good reason to delay pushing

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia, as it does not decrease the rate of spontaneous vaginal delivery. It does, however, increase the length of second stage labor and the risk of postpartum hemorrhage and chorioamnionitis.

CAVEATS

Study was stopped early, and groups were unblinded

This study was stopped early, so it is not known if it was underpowered for some of the secondary outcomes. Also, it was not possible to blind the groups, so it is not clear if any bias in patient management or diagnosis resulted.

CHALLENGES TO IMPLEMENTATION

Will current practice and culture pose obstacles?

Although the overt challenges to enacting a policy of immediate pushing are minimal, the inertia of current practice and culture could affect the implementation of this strategy.

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.

ILLUSTRATIVE CASE

A 27-year-old G1P000 at term with an uncomplicated pregnancy has been laboring for 6 hours with an epidural in place and a reassuring fetal heart tracing. She is at –2 station with complete cervical dilation and effacement. Should she push now or delay pushing to allow for more descent?

More than 10,000 women give birth each day in the United States, yet few of our approaches to labor management are evidence based.² For example, there are no clear guidelines on whether immediate pushing or delayed pushing (waiting 1-2 hours) in the second stage of labor (the time from complete cervical dilation to delivery of the fetus) leads to better outcomes.

A recent Cochrane review, which included very low- to moderate-quality trials of nulliparous and multiparous women using epidural analgesia showed that delayed pushing resulted in more vaginal deliveries, longer duration of second stage of labor, and shorter duration of pushing.³ But many of the trials included in this Cochrane review were noted to have study design limitations and significant heterogeneity.

A recent retrospective study found that delayed pushing resulted in longer duration of pushing and increased risks for cesarean section, operative vaginal delivery, and postpartum hemorrhage in nulliparous patients with and without epidurals.⁴ The World Health Organization recommends delayed pushing in women with epidural analgesia if time and fetal monitoring resources are available.⁵

STUDY SUMMARY

Does the timing of second stage pushing efforts affect outcomes?

This multicenter randomized controlled trial (RCT) evaluated the effect on spontaneous vaginal delivery of delayed pushing vs immediate pushing in 2404 term nulliparous women using epidural analgesia.¹ Patients were ≥ 37 weeks’ gestation. Once patients achieved 10 cm of cervical dilation, they were randomized in a 1:1 ratio to either immediate pushing or to delayed (for 60 minutes) pushing (unless there was an irresistible urge to push or they were otherwise instructed by their provider).

Outcome and results. The primary outcome was spontaneous vaginal delivery without the use of any operative support. The mean time to pushing after complete cervical dilation was 19 minutes in the immediate pushing group and 60 minutes in the delayed group. There was no difference in the rate of spontaneous vaginal delivery between the immediate and delayed pushing groups (86% vs 87%, respectively; P = .67). The immediate pushing group had a shorter duration of second stage of labor (102 minutes vs 134 minutes; mean difference [MD] = –32 minutes; 95% confidence interval [CI], –37 to –27; P < .001) and a slightly longer duration of active pushing (84 minutes vs 75 minutes; MD = 9.2 minutes; 95% CI, 6-13; P < .001).

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia.

There was no significant difference in operative vaginal or cesarean deliveries. Postpartum hemorrhage was lower in the immediate pushing group (2.3% vs 4%; risk ratio [RR] = 0.6; 95% CI, 0.3-0.9; P = .03; number needed to treat [NNT] = 58), as was chorioamnionitis (6.7% vs 9.1%; RR = 0.7; 95% CI, 0.66-0.90; P = .005; NNT = 40). There was no significant difference in neonatal morbidity between groups. And in subgroup analysis, there was no significant difference in rates of vaginal delivery based on fetal position (occiput anterior, posterior, or transverse) or station (defined as high [< 2 cm] or low [≥ 2 cm]) between groups. Recruitment was stopped early at 75% because there was no difference in the primary outcome and there was concern regarding an increased risk of hemorrhage in the delayed pushing group.

Continue to: WHAT'S NEW

WHAT’S NEW

There’s no good reason to delay pushing

Delaying pushing once the cervix is completely dilated is not indicated, even for nulliparous women receiving epidural analgesia, as it does not decrease the rate of spontaneous vaginal delivery. It does, however, increase the length of second stage labor and the risk of postpartum hemorrhage and chorioamnionitis.

CAVEATS

Study was stopped early, and groups were unblinded

This study was stopped early, so it is not known if it was underpowered for some of the secondary outcomes. Also, it was not possible to blind the groups, so it is not clear if any bias in patient management or diagnosis resulted.

CHALLENGES TO IMPLEMENTATION

Will current practice and culture pose obstacles?

Although the overt challenges to enacting a policy of immediate pushing are minimal, the inertia of current practice and culture could affect the implementation of this strategy.

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.

Too few patients are being screened for abdominal aortic aneurysm (AAA), resulting in severe morbidity and mortality. Many patients with AAA aren’t identified until they present with rupture, leading to mortality as high as 90%.¹ Early detection is critical.

Medicare offers one-time free screening to eligible individuals > 65 years of age, and several professional organizations promote screening with published guidelines, which we discuss later in this article.

So who is at risk, who should be screened, and what is the best way to screen your patients?

Risk factors and sex differences

AAA has a prevalence of between 1% and 5% in men > 65 years old,^2,3 and it is 4 to 6 times more common in men than women.⁴ Major risk factors include smoking, older age, family history, and genetic factors, while hypertension, history of coronary artery disease, hyperlipidemia, and peripheral arterial disease have weaker associations.^3,4 Exercise and diabetes seem to have protective effects.⁵

The incidence and mortality of AAA increased between the 1950s and the mid-1990s; however, both indicators have decreased in numerous countries in the 21st century.⁶ Although the prevalence is much lower in women, they have a higher risk of rupture than men at equivalent lesion diameters.³ The prevalence of AAA in women who smoke and are > 70 years of age is > 1%.³

Silent but deadly

Most patients with AAA are asymptomatic. Their lesions are often detected incidentally on magnetic resonance imaging of the spine obtained for back pain, on an abdominal ultrasound (US) for gallstones, or on a routine computed tomography (CT) scan for the evaluation of abdominal pain. Some patients will experience vague abdominal discomfort from rapid expansion of an aneurysm prior to rupture, necessitating urgent repair. Also, some large aneurysms can erode into the spine and cause chronic back pain prior to rupture. An infrarenal abdominal aortic diameter > 30 mm defines an aneurysm,⁷ and once the diameter reaches 55 mm, the threat of rupture often justifies operative repair. (See “The preferred approach to repair.”)

Ruptured aneurysms will classically manifest with severe abdominal and/or back pain. Often a ruptured aneurysm will be contained in the retroperitoneum, allowing the patient to remain hemodynamically stable for a period of time and thus providing a window of opportunity for emergent repair.

Continue to: What is the evidence that screening is effective?

 

 

What is the evidence that screening is effective?

In 1988, researchers in Chichester, England, randomized > 6000 men ages 65 to 80 years to either a control group or a group that was offered a one-time US screen for AAA. After 15 years of follow-up, no significant difference in AAA mortality was seen between the groups, although 26% of those invited for screening declined to participate and accounted for more than half of the AAA-related deaths in the group receiving an invitation for screening.⁸

The MASS Trial,⁹ another British study, began in 1997 and screened men ages 65 to 74. More than 67,000 men were randomized, with 1 group invited for AAA screening and the other serving as a control. The final report on this trial was published in 2012. After 13 years of follow-up, there was a 42% reduction in AAA-related deaths in the group invited for screening, a small reduction in all-cause mortality, and a significant reduction in risk of AAA rupture (hazard ratio = 0.57). The researchers noted that 216 patients would have to be invited for screening to prevent 1 death over 13 years. They also reported that 21% of the invited patients that had an AAA-related death had an initial scan that was negative for AAA (aortic diameter < 3 cm). However, despite this finding, screening still appeared to be beneficial.

Lindholdt et al¹⁰ randomized > 12,000 Danish men ages 64 to 73 to serve as controls or to be invited for US screening for AAA. After 13 years of follow-up, those invited for screening had a 66% relative risk reduction in AAA-related mortality, with screening considered cost effective. There were no differences between the groups in all-cause mortality. Conversely, the Western Australia Trial studied an older group of men, ages 64 to 83, but was unable to show a benefit of screening in lowering AAA-related mortality.¹¹

Tikagi et al⁶ performed a meta-analysis on the data from the 4 trials above and reported up to 15 years of follow-up. Patients who attended screening sessions had a reduction in all-cause mortality with an odds ratio (OR) of 0.6, and a marked reduction in AAA-­related mortality with an OR of 0.4. The favorable data on screening have prompted the United Kingdom and Sweden to offer screening to all men ≥ 65 years, based on the current estimate of a 1% prevalence of AAA, although screening is felt to remain cost effective down to a prevalence of 0.35%.¹²

Handheld ultrasound is a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.

Massachusetts General Hospital also reported¹³ that the detection rate of AAA increased, with the diagnosis made at smaller aneurysm dimensions, following publication of the US Preventive Services Task Force recommendations (reviewed below).

Continue to: When to screen

When to screen

Several professional organizations, as well as Medicare, have published AAA screening recommendations. While there are notable differences among them, their shared message is crucial: screen. Consider adding applicable reminders to your practice’s electronic medical record system to increase screening rates for eligible patients.

US Preventive Services Task Force ¹⁴

• Recommend one-time AAA screening with ultrasonography for men ages 65 to 75 years who have ever smoked (B recommendation).
• Selectively offer AAA screening to men ages 65 to 75 years who have never smoked, rather than routinely screening all men in this group (C recommendation). Individual attributes that could favor screening include a family history of AAA, the presence of other arterial aneurysms, and the number of risk factors for cardiovascular disease.
• Do not routinely screen women for AAA if they have never smoked and have no family history of AAA (D recommendation). For women ages 65 to 75 years who have ever smoked or have a family history of AAA, current evidence is insufficient to assess the balance of benefits and harms of screening for AAA (I statement). (See the related Practice Alert.)

Canadian Task Force on Preventive Health Care⁴

• Recommend one-time screening for AAA with US for men 65 to 80 years of age (weak level of recommendation; moderate-quality evidence).
• Do not recommend screening for men older than 80 years of age (weak recommendation; low quality of evidence).
• Do not recommend screening for women (strong recommendation; very low quality of evidence).

Society for Vascular Surgery¹⁵

• Recommend one-time US screening for AAA for men or women 65 to 75 years of age with a history of tobacco use (strong recommendation with high-quality evidence).
• Recommend one-time screening if there is a history of smoking for men or women > 75 years of age who are in good health and have not previously been screened. (Weak recommendation with low-quality evidence).
• Recommend one-time screening of men or women 65 to 75 years of age who are first-degree relatives of someone with AAA, or in those older than age 75 and in good health (weak recommendation with low-quality evidence).

How to screen

Physical exam. The abdominal aorta is often palpable in the epigastric region, and a thorough abdominal exam should include an attempt to detect it. It is critical that the patient be supine during palpation, to allow compression of the aorta against the lumbar spine. Even with a well-performed exam, however, its sensitivity is just 76% in the detection of AAA ≥ 5 cm.¹⁶

Continue to: Imaging

Imaging. US is the preferred imaging procedure when screening for AAA, given its high sensitivity and specificity.¹⁷ If US yields poor image quality, noncontrast CT is suggested, with magnetic resonance angiography being another alternative.¹⁸ Handheld US has the potential to supplement the physical exam, and has been shown to be a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.¹⁹ Typically, a formal aortic US requires a patient to go without food or liquids for 8 hours before the procedure to obtain the best image; however, a good estimate of aortic diameter can be obtained without this restriction.

Despite Medicare coverage and recs, few people are screened

In 2007, Medicare started the SAAVE Program (Screening Aortic Aneurysm Very Effectively), offering a one-time US screening for AAA for eligible patients, as part of the Welcome to Medicare Program. Eligible individuals are men between 65 and 75 years of age with a history of smoking at least 100 cigarettes in their lifetime, and men or women in the same age group with a family history of AAA.²

Despite these recommendations, few patients receive screening. Centers for Medicare & Medicaid Services data show that < 10% of eligible men were screened between 2004 and 2008,²⁰ and Olchanski et al²¹ report that < 1% of eligible patients were screened from 2005-2009. A simulation model estimates that 131 additional life years could be gained per 1000 patients screened if the utilization rate could be increased to 80%, a seemingly achievable goal.²¹ Moreover, expanding the screening program to include female smokers could increase 10-year life expectancy by 13%.²¹ Reasons for underutilization of this Medicare screening benefit may include lack of awareness by physicians and patients, costs of co-pays, and underutilization of the basic Welcome to Medicare exam.²¹

An additional consequence of low utilization of AAA screening is a high percentage of patients who are identified only late in the course of the disease. Mell et al²² report that 39% of patients undergoing AAA repair were identified < 6 months prior to surgery, a higher percentage than would be expected in a well-screened population. They also determined that slightly more than one-third of patients undergoing surgery for ruptured AAA had diagnostic imaging performed > 6 months prior to surgery, suggesting the possibility that these patients may not have been properly surveilled for aneurysm expansion, although the authors note that other potential explanations include delays in treatment due to comorbidities, and patient-related factors such as refusal of surgery or noncompliance with follow-up.

CORRESPONDENCE
Jeffrey S. Todd, MD, 127 McClanahan Street, Suite 300, Roanoke, VA 24014; jstodd@carilionclinic.org.

Too few patients are being screened for abdominal aortic aneurysm (AAA), resulting in severe morbidity and mortality. Many patients with AAA aren’t identified until they present with rupture, leading to mortality as high as 90%.¹ Early detection is critical.

Medicare offers one-time free screening to eligible individuals > 65 years of age, and several professional organizations promote screening with published guidelines, which we discuss later in this article.

So who is at risk, who should be screened, and what is the best way to screen your patients?

Risk factors and sex differences

AAA has a prevalence of between 1% and 5% in men > 65 years old,^2,3 and it is 4 to 6 times more common in men than women.⁴ Major risk factors include smoking, older age, family history, and genetic factors, while hypertension, history of coronary artery disease, hyperlipidemia, and peripheral arterial disease have weaker associations.^3,4 Exercise and diabetes seem to have protective effects.⁵

The incidence and mortality of AAA increased between the 1950s and the mid-1990s; however, both indicators have decreased in numerous countries in the 21st century.⁶ Although the prevalence is much lower in women, they have a higher risk of rupture than men at equivalent lesion diameters.³ The prevalence of AAA in women who smoke and are > 70 years of age is > 1%.³

Silent but deadly

Most patients with AAA are asymptomatic. Their lesions are often detected incidentally on magnetic resonance imaging of the spine obtained for back pain, on an abdominal ultrasound (US) for gallstones, or on a routine computed tomography (CT) scan for the evaluation of abdominal pain. Some patients will experience vague abdominal discomfort from rapid expansion of an aneurysm prior to rupture, necessitating urgent repair. Also, some large aneurysms can erode into the spine and cause chronic back pain prior to rupture. An infrarenal abdominal aortic diameter > 30 mm defines an aneurysm,⁷ and once the diameter reaches 55 mm, the threat of rupture often justifies operative repair. (See “The preferred approach to repair.”)

Ruptured aneurysms will classically manifest with severe abdominal and/or back pain. Often a ruptured aneurysm will be contained in the retroperitoneum, allowing the patient to remain hemodynamically stable for a period of time and thus providing a window of opportunity for emergent repair.

Continue to: What is the evidence that screening is effective?

 

 

What is the evidence that screening is effective?

In 1988, researchers in Chichester, England, randomized > 6000 men ages 65 to 80 years to either a control group or a group that was offered a one-time US screen for AAA. After 15 years of follow-up, no significant difference in AAA mortality was seen between the groups, although 26% of those invited for screening declined to participate and accounted for more than half of the AAA-related deaths in the group receiving an invitation for screening.⁸

The MASS Trial,⁹ another British study, began in 1997 and screened men ages 65 to 74. More than 67,000 men were randomized, with 1 group invited for AAA screening and the other serving as a control. The final report on this trial was published in 2012. After 13 years of follow-up, there was a 42% reduction in AAA-related deaths in the group invited for screening, a small reduction in all-cause mortality, and a significant reduction in risk of AAA rupture (hazard ratio = 0.57). The researchers noted that 216 patients would have to be invited for screening to prevent 1 death over 13 years. They also reported that 21% of the invited patients that had an AAA-related death had an initial scan that was negative for AAA (aortic diameter < 3 cm). However, despite this finding, screening still appeared to be beneficial.

Lindholdt et al¹⁰ randomized > 12,000 Danish men ages 64 to 73 to serve as controls or to be invited for US screening for AAA. After 13 years of follow-up, those invited for screening had a 66% relative risk reduction in AAA-related mortality, with screening considered cost effective. There were no differences between the groups in all-cause mortality. Conversely, the Western Australia Trial studied an older group of men, ages 64 to 83, but was unable to show a benefit of screening in lowering AAA-related mortality.¹¹

Tikagi et al⁶ performed a meta-analysis on the data from the 4 trials above and reported up to 15 years of follow-up. Patients who attended screening sessions had a reduction in all-cause mortality with an odds ratio (OR) of 0.6, and a marked reduction in AAA-­related mortality with an OR of 0.4. The favorable data on screening have prompted the United Kingdom and Sweden to offer screening to all men ≥ 65 years, based on the current estimate of a 1% prevalence of AAA, although screening is felt to remain cost effective down to a prevalence of 0.35%.¹²

Handheld ultrasound is a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.

Massachusetts General Hospital also reported¹³ that the detection rate of AAA increased, with the diagnosis made at smaller aneurysm dimensions, following publication of the US Preventive Services Task Force recommendations (reviewed below).

Continue to: When to screen

When to screen

Several professional organizations, as well as Medicare, have published AAA screening recommendations. While there are notable differences among them, their shared message is crucial: screen. Consider adding applicable reminders to your practice’s electronic medical record system to increase screening rates for eligible patients.

US Preventive Services Task Force ¹⁴

• Recommend one-time AAA screening with ultrasonography for men ages 65 to 75 years who have ever smoked (B recommendation).
• Selectively offer AAA screening to men ages 65 to 75 years who have never smoked, rather than routinely screening all men in this group (C recommendation). Individual attributes that could favor screening include a family history of AAA, the presence of other arterial aneurysms, and the number of risk factors for cardiovascular disease.
• Do not routinely screen women for AAA if they have never smoked and have no family history of AAA (D recommendation). For women ages 65 to 75 years who have ever smoked or have a family history of AAA, current evidence is insufficient to assess the balance of benefits and harms of screening for AAA (I statement). (See the related Practice Alert.)

Canadian Task Force on Preventive Health Care⁴

• Recommend one-time screening for AAA with US for men 65 to 80 years of age (weak level of recommendation; moderate-quality evidence).
• Do not recommend screening for men older than 80 years of age (weak recommendation; low quality of evidence).
• Do not recommend screening for women (strong recommendation; very low quality of evidence).

Society for Vascular Surgery¹⁵

• Recommend one-time US screening for AAA for men or women 65 to 75 years of age with a history of tobacco use (strong recommendation with high-quality evidence).
• Recommend one-time screening if there is a history of smoking for men or women > 75 years of age who are in good health and have not previously been screened. (Weak recommendation with low-quality evidence).
• Recommend one-time screening of men or women 65 to 75 years of age who are first-degree relatives of someone with AAA, or in those older than age 75 and in good health (weak recommendation with low-quality evidence).

How to screen

Physical exam. The abdominal aorta is often palpable in the epigastric region, and a thorough abdominal exam should include an attempt to detect it. It is critical that the patient be supine during palpation, to allow compression of the aorta against the lumbar spine. Even with a well-performed exam, however, its sensitivity is just 76% in the detection of AAA ≥ 5 cm.¹⁶

Continue to: Imaging

Imaging. US is the preferred imaging procedure when screening for AAA, given its high sensitivity and specificity.¹⁷ If US yields poor image quality, noncontrast CT is suggested, with magnetic resonance angiography being another alternative.¹⁸ Handheld US has the potential to supplement the physical exam, and has been shown to be a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.¹⁹ Typically, a formal aortic US requires a patient to go without food or liquids for 8 hours before the procedure to obtain the best image; however, a good estimate of aortic diameter can be obtained without this restriction.

Despite Medicare coverage and recs, few people are screened

In 2007, Medicare started the SAAVE Program (Screening Aortic Aneurysm Very Effectively), offering a one-time US screening for AAA for eligible patients, as part of the Welcome to Medicare Program. Eligible individuals are men between 65 and 75 years of age with a history of smoking at least 100 cigarettes in their lifetime, and men or women in the same age group with a family history of AAA.²

Despite these recommendations, few patients receive screening. Centers for Medicare & Medicaid Services data show that < 10% of eligible men were screened between 2004 and 2008,²⁰ and Olchanski et al²¹ report that < 1% of eligible patients were screened from 2005-2009. A simulation model estimates that 131 additional life years could be gained per 1000 patients screened if the utilization rate could be increased to 80%, a seemingly achievable goal.²¹ Moreover, expanding the screening program to include female smokers could increase 10-year life expectancy by 13%.²¹ Reasons for underutilization of this Medicare screening benefit may include lack of awareness by physicians and patients, costs of co-pays, and underutilization of the basic Welcome to Medicare exam.²¹

An additional consequence of low utilization of AAA screening is a high percentage of patients who are identified only late in the course of the disease. Mell et al²² report that 39% of patients undergoing AAA repair were identified < 6 months prior to surgery, a higher percentage than would be expected in a well-screened population. They also determined that slightly more than one-third of patients undergoing surgery for ruptured AAA had diagnostic imaging performed > 6 months prior to surgery, suggesting the possibility that these patients may not have been properly surveilled for aneurysm expansion, although the authors note that other potential explanations include delays in treatment due to comorbidities, and patient-related factors such as refusal of surgery or noncompliance with follow-up.

CORRESPONDENCE
Jeffrey S. Todd, MD, 127 McClanahan Street, Suite 300, Roanoke, VA 24014; jstodd@carilionclinic.org.

Too few patients are being screened for abdominal aortic aneurysm (AAA), resulting in severe morbidity and mortality. Many patients with AAA aren’t identified until they present with rupture, leading to mortality as high as 90%.¹ Early detection is critical.

Medicare offers one-time free screening to eligible individuals > 65 years of age, and several professional organizations promote screening with published guidelines, which we discuss later in this article.

So who is at risk, who should be screened, and what is the best way to screen your patients?

Risk factors and sex differences

AAA has a prevalence of between 1% and 5% in men > 65 years old,^2,3 and it is 4 to 6 times more common in men than women.⁴ Major risk factors include smoking, older age, family history, and genetic factors, while hypertension, history of coronary artery disease, hyperlipidemia, and peripheral arterial disease have weaker associations.^3,4 Exercise and diabetes seem to have protective effects.⁵

The incidence and mortality of AAA increased between the 1950s and the mid-1990s; however, both indicators have decreased in numerous countries in the 21st century.⁶ Although the prevalence is much lower in women, they have a higher risk of rupture than men at equivalent lesion diameters.³ The prevalence of AAA in women who smoke and are > 70 years of age is > 1%.³

Silent but deadly

Most patients with AAA are asymptomatic. Their lesions are often detected incidentally on magnetic resonance imaging of the spine obtained for back pain, on an abdominal ultrasound (US) for gallstones, or on a routine computed tomography (CT) scan for the evaluation of abdominal pain. Some patients will experience vague abdominal discomfort from rapid expansion of an aneurysm prior to rupture, necessitating urgent repair. Also, some large aneurysms can erode into the spine and cause chronic back pain prior to rupture. An infrarenal abdominal aortic diameter > 30 mm defines an aneurysm,⁷ and once the diameter reaches 55 mm, the threat of rupture often justifies operative repair. (See “The preferred approach to repair.”)

Ruptured aneurysms will classically manifest with severe abdominal and/or back pain. Often a ruptured aneurysm will be contained in the retroperitoneum, allowing the patient to remain hemodynamically stable for a period of time and thus providing a window of opportunity for emergent repair.

Continue to: What is the evidence that screening is effective?

 

 

What is the evidence that screening is effective?

In 1988, researchers in Chichester, England, randomized > 6000 men ages 65 to 80 years to either a control group or a group that was offered a one-time US screen for AAA. After 15 years of follow-up, no significant difference in AAA mortality was seen between the groups, although 26% of those invited for screening declined to participate and accounted for more than half of the AAA-related deaths in the group receiving an invitation for screening.⁸

The MASS Trial,⁹ another British study, began in 1997 and screened men ages 65 to 74. More than 67,000 men were randomized, with 1 group invited for AAA screening and the other serving as a control. The final report on this trial was published in 2012. After 13 years of follow-up, there was a 42% reduction in AAA-related deaths in the group invited for screening, a small reduction in all-cause mortality, and a significant reduction in risk of AAA rupture (hazard ratio = 0.57). The researchers noted that 216 patients would have to be invited for screening to prevent 1 death over 13 years. They also reported that 21% of the invited patients that had an AAA-related death had an initial scan that was negative for AAA (aortic diameter < 3 cm). However, despite this finding, screening still appeared to be beneficial.

Lindholdt et al¹⁰ randomized > 12,000 Danish men ages 64 to 73 to serve as controls or to be invited for US screening for AAA. After 13 years of follow-up, those invited for screening had a 66% relative risk reduction in AAA-related mortality, with screening considered cost effective. There were no differences between the groups in all-cause mortality. Conversely, the Western Australia Trial studied an older group of men, ages 64 to 83, but was unable to show a benefit of screening in lowering AAA-related mortality.¹¹

Tikagi et al⁶ performed a meta-analysis on the data from the 4 trials above and reported up to 15 years of follow-up. Patients who attended screening sessions had a reduction in all-cause mortality with an odds ratio (OR) of 0.6, and a marked reduction in AAA-­related mortality with an OR of 0.4. The favorable data on screening have prompted the United Kingdom and Sweden to offer screening to all men ≥ 65 years, based on the current estimate of a 1% prevalence of AAA, although screening is felt to remain cost effective down to a prevalence of 0.35%.¹²

Handheld ultrasound is a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.

Massachusetts General Hospital also reported¹³ that the detection rate of AAA increased, with the diagnosis made at smaller aneurysm dimensions, following publication of the US Preventive Services Task Force recommendations (reviewed below).

Continue to: When to screen

When to screen

Several professional organizations, as well as Medicare, have published AAA screening recommendations. While there are notable differences among them, their shared message is crucial: screen. Consider adding applicable reminders to your practice’s electronic medical record system to increase screening rates for eligible patients.

US Preventive Services Task Force ¹⁴

• Recommend one-time AAA screening with ultrasonography for men ages 65 to 75 years who have ever smoked (B recommendation).
• Selectively offer AAA screening to men ages 65 to 75 years who have never smoked, rather than routinely screening all men in this group (C recommendation). Individual attributes that could favor screening include a family history of AAA, the presence of other arterial aneurysms, and the number of risk factors for cardiovascular disease.
• Do not routinely screen women for AAA if they have never smoked and have no family history of AAA (D recommendation). For women ages 65 to 75 years who have ever smoked or have a family history of AAA, current evidence is insufficient to assess the balance of benefits and harms of screening for AAA (I statement). (See the related Practice Alert.)

Canadian Task Force on Preventive Health Care⁴

• Recommend one-time screening for AAA with US for men 65 to 80 years of age (weak level of recommendation; moderate-quality evidence).
• Do not recommend screening for men older than 80 years of age (weak recommendation; low quality of evidence).
• Do not recommend screening for women (strong recommendation; very low quality of evidence).

Society for Vascular Surgery¹⁵

• Recommend one-time US screening for AAA for men or women 65 to 75 years of age with a history of tobacco use (strong recommendation with high-quality evidence).
• Recommend one-time screening if there is a history of smoking for men or women > 75 years of age who are in good health and have not previously been screened. (Weak recommendation with low-quality evidence).
• Recommend one-time screening of men or women 65 to 75 years of age who are first-degree relatives of someone with AAA, or in those older than age 75 and in good health (weak recommendation with low-quality evidence).

How to screen

Physical exam. The abdominal aorta is often palpable in the epigastric region, and a thorough abdominal exam should include an attempt to detect it. It is critical that the patient be supine during palpation, to allow compression of the aorta against the lumbar spine. Even with a well-performed exam, however, its sensitivity is just 76% in the detection of AAA ≥ 5 cm.¹⁶

Continue to: Imaging

Imaging. US is the preferred imaging procedure when screening for AAA, given its high sensitivity and specificity.¹⁷ If US yields poor image quality, noncontrast CT is suggested, with magnetic resonance angiography being another alternative.¹⁸ Handheld US has the potential to supplement the physical exam, and has been shown to be a viable method to detect AAA in an outpatient primary care setting at a reasonable cost.¹⁹ Typically, a formal aortic US requires a patient to go without food or liquids for 8 hours before the procedure to obtain the best image; however, a good estimate of aortic diameter can be obtained without this restriction.

Despite Medicare coverage and recs, few people are screened

In 2007, Medicare started the SAAVE Program (Screening Aortic Aneurysm Very Effectively), offering a one-time US screening for AAA for eligible patients, as part of the Welcome to Medicare Program. Eligible individuals are men between 65 and 75 years of age with a history of smoking at least 100 cigarettes in their lifetime, and men or women in the same age group with a family history of AAA.²

Despite these recommendations, few patients receive screening. Centers for Medicare & Medicaid Services data show that < 10% of eligible men were screened between 2004 and 2008,²⁰ and Olchanski et al²¹ report that < 1% of eligible patients were screened from 2005-2009. A simulation model estimates that 131 additional life years could be gained per 1000 patients screened if the utilization rate could be increased to 80%, a seemingly achievable goal.²¹ Moreover, expanding the screening program to include female smokers could increase 10-year life expectancy by 13%.²¹ Reasons for underutilization of this Medicare screening benefit may include lack of awareness by physicians and patients, costs of co-pays, and underutilization of the basic Welcome to Medicare exam.²¹

An additional consequence of low utilization of AAA screening is a high percentage of patients who are identified only late in the course of the disease. Mell et al²² report that 39% of patients undergoing AAA repair were identified < 6 months prior to surgery, a higher percentage than would be expected in a well-screened population. They also determined that slightly more than one-third of patients undergoing surgery for ruptured AAA had diagnostic imaging performed > 6 months prior to surgery, suggesting the possibility that these patients may not have been properly surveilled for aneurysm expansion, although the authors note that other potential explanations include delays in treatment due to comorbidities, and patient-related factors such as refusal of surgery or noncompliance with follow-up.

CORRESPONDENCE
Jeffrey S. Todd, MD, 127 McClanahan Street, Suite 300, Roanoke, VA 24014; jstodd@carilionclinic.org.

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

 

 

RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

 

 

RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

EVIDENCE SUMMARY

A Cochrane systematic review of vitamin D for managing asthma performed meta-analyses on RCTs that evaluated several outcomes.¹ The review found improvement in the primary outcome of asthma exacerbations requiring systemic steroids, mainly in adult patients, and in the secondary outcomes of emergency department visits or hospitalization, in a mix of adults and children (TABLE^1-6).

Most participants had mild-to-moderate asthma; trials lasted 4 to 12 months. Vitamin D dosage regimens varied, with a median daily dose of 900 IU/d (range, 400-4000 IU/d). Six RCTs were rated high-quality, and 1 had unclear risk of bias.

Supplementation reduced exacerbations in patients with low vitamin D levels

A subsequent (2017) systematic review and meta-analysis evaluating the primary outcome of exacerbations requiring steroids⁷ included another study⁸ (in addition to the 6 RCTs in the Cochrane review).

When researchers reanalyzed individual participant data from the trials in the Cochrane review, plus the additional RCT, to include baseline vitamin D levels, they found that vitamin D supplementation reduced exacerbations overall (NNT = 7.7) and in patients with low baseline vitamin D levels (25[OH] vitamin D < 25 nmol/L; 92 participants in 3 RCTs; NNT = 4.3) but not in patients with higher baseline levels (764 participants in 6 RCTs). Vitamin D supplementation reduced the asthma exacerbation rate in patients with low baseline vitamin D levels (0.19 vs 0.42 events per participant-year; P = .046).

Smaller benefit found on ED visits and hospitalizations

The Cochrane review, with 2 RCTs with adults (n = 658)¹ and 5 RCTs with children (n = 305),^2-6 evaluated whether Vitamin D reduced the need for emergency department visits and hospitalization with asthma exacerbations; they found a smaller benefit (NNT = 26.3).

Effects on FEV₁, daily asthma symptoms, and serious adverse effects

Several RCTs included in the 2017 meta-analysis found no effect of vitamin D supplementation on FEV₁, daily asthma symptoms (evaluated with the standardized Asthma Control Test Score), or reported serious adverse events.^2-6,9,10 No deaths occurred in any trial.

Additional findings in children from lower-quality studies

A 2015 systematic review and meta-analysis of RCTs evaluating vitamin D supplementation for children with asthma found¹¹:

• moderate-quality evidence for decreased emergency department visits (1 RCT from India, 100 children ages 3 to 14 years, decrease not specified; P = .015);
• low-quality evidence for reduced exacerbations (6 RCTs [3 RCTs also in Cochrane review], 507 children ages 3 to 17 years; risk ratio = 0.41; 95% confidence interval, 0.27-0.63); and
• low-quality evidence for reduced standardized asthma symptom scores (6 RCTs [2 RCTs also in Cochrane review], 231 children ages 3 to 17 years; amount of reduction not listed; P = .01).

Continue to: RECOMMENDATIONS

 

 

RECOMMENDATIONS

No published guidelines discuss using vitamin D in managing asthma. An American Academy of Family Physicians (AAFP) summary of the Cochrane systematic review recommends that family physicians await further studies and updated guidelines before recommending vitamin D for patients with asthma.¹² The AAFP also points out that the Endocrine Society has recommended vitamin D supplementation for adults (1500-2000 IU/d) and children (at least 1000 IU/d) at risk for deficiency.

Editor's takeaway

In the meta-analyses highlighted here, researchers evaluated asthma patients with a wide range of ages, baseline vitamin D levels, and vitamin D supplementation protocols. Although vitamin D reduced asthma exacerbations requiring steroids overall, the effect was driven by 3 studies of patients with low baseline vitamin D levels. As a result, disentangling who might benefit the most remains a challenge. The conservative course for now is to manage asthma according to current guidelines and supplement vitamin D in patients at risk for, or with known, ­deficiency.

The Food and Drug Administration has announced a new approved indication for olaparib (Lynparza) in adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Olaparib is now FDA-approved for use in combination with bevacizumab as maintenance therapy in patients who responded to first-line platinum-based chemotherapy and whose cancer is homologous recombination deficiency positive, as defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability.

The FDA also approved the Myriad myChoice CDx test as a companion diagnostic for olaparib.

Trial results

The efficacy of olaparib and the myChoice CDx test were assessed in patients in the phase 3 PAOLA-1 trial (NCT02477644). The study enrolled patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received first-line platinum-based chemotherapy and bevacizumab.

Patients were stratified by first-line treatment outcome and BRCA mutation status, as determined by prospective local testing. All available clinical samples were retrospectively tested with the Myriad myChoice CDx test.

The patients were randomized to receive olaparib at 300 mg orally twice daily in combination with bevacizumab at 15 mg/kg every 3 weeks (n = 537) or placebo plus bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started olaparib 3-9 weeks after their last chemotherapy dose. Olaparib could be continued for up to 2 years or until disease progression or unacceptable toxicity.

The median progression-free survival among the 387 patients with homologous recombination deficiency-positive tumors was 37.2 months in the olaparib arm and 17.7 months in the placebo arm (hazard ratio, 0.33), according to the prescribing information for olaparib.

Serious adverse events occurred in 31% of patients in the olaparib arm. The most common were hypertension (19%) and anemia (17%).

Dose interruptions from adverse events occurred in 54% of patients in the olaparib arm, and dose reductions from adverse events occurred in 41%.

jensmith@mdedge.com

The Food and Drug Administration has announced a new approved indication for olaparib (Lynparza) in adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Olaparib is now FDA-approved for use in combination with bevacizumab as maintenance therapy in patients who responded to first-line platinum-based chemotherapy and whose cancer is homologous recombination deficiency positive, as defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability.

The FDA also approved the Myriad myChoice CDx test as a companion diagnostic for olaparib.

Trial results

The efficacy of olaparib and the myChoice CDx test were assessed in patients in the phase 3 PAOLA-1 trial (NCT02477644). The study enrolled patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received first-line platinum-based chemotherapy and bevacizumab.

Patients were stratified by first-line treatment outcome and BRCA mutation status, as determined by prospective local testing. All available clinical samples were retrospectively tested with the Myriad myChoice CDx test.

The patients were randomized to receive olaparib at 300 mg orally twice daily in combination with bevacizumab at 15 mg/kg every 3 weeks (n = 537) or placebo plus bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started olaparib 3-9 weeks after their last chemotherapy dose. Olaparib could be continued for up to 2 years or until disease progression or unacceptable toxicity.

The median progression-free survival among the 387 patients with homologous recombination deficiency-positive tumors was 37.2 months in the olaparib arm and 17.7 months in the placebo arm (hazard ratio, 0.33), according to the prescribing information for olaparib.

Serious adverse events occurred in 31% of patients in the olaparib arm. The most common were hypertension (19%) and anemia (17%).

Dose interruptions from adverse events occurred in 54% of patients in the olaparib arm, and dose reductions from adverse events occurred in 41%.

jensmith@mdedge.com

The Food and Drug Administration has announced a new approved indication for olaparib (Lynparza) in adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Olaparib is now FDA-approved for use in combination with bevacizumab as maintenance therapy in patients who responded to first-line platinum-based chemotherapy and whose cancer is homologous recombination deficiency positive, as defined by a deleterious or suspected deleterious BRCA mutation and/or genomic instability.

The FDA also approved the Myriad myChoice CDx test as a companion diagnostic for olaparib.

Trial results

The efficacy of olaparib and the myChoice CDx test were assessed in patients in the phase 3 PAOLA-1 trial (NCT02477644). The study enrolled patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received first-line platinum-based chemotherapy and bevacizumab.

Patients were stratified by first-line treatment outcome and BRCA mutation status, as determined by prospective local testing. All available clinical samples were retrospectively tested with the Myriad myChoice CDx test.

The patients were randomized to receive olaparib at 300 mg orally twice daily in combination with bevacizumab at 15 mg/kg every 3 weeks (n = 537) or placebo plus bevacizumab (n = 269). Patients continued bevacizumab in the maintenance setting and started olaparib 3-9 weeks after their last chemotherapy dose. Olaparib could be continued for up to 2 years or until disease progression or unacceptable toxicity.

The median progression-free survival among the 387 patients with homologous recombination deficiency-positive tumors was 37.2 months in the olaparib arm and 17.7 months in the placebo arm (hazard ratio, 0.33), according to the prescribing information for olaparib.

Serious adverse events occurred in 31% of patients in the olaparib arm. The most common were hypertension (19%) and anemia (17%).

Dose interruptions from adverse events occurred in 54% of patients in the olaparib arm, and dose reductions from adverse events occurred in 41%.

jensmith@mdedge.com

U.S. Supreme Court justices appear divided over whether the Trump administration acted properly when it expanded exemptions under the Affordable Care Act’s contraception mandate.

jsmith/iStockphoto

During oral arguments on May 6, the court expressed differing perspectives about the administration’s authority to allow for more exemptions under the health law’s birth control mandate and whether the expansions were reasonable. Justices heard the consolidated cases – Little Sisters of the Poor v. Pennsylvania and Trump v. Pennsylvania – by teleconference because of the COVID-19 pandemic. They are expected to make a decision by the summer.

Associate justice Ruth Bader Ginsburg, who participated in the telephone conference call from a hospital where she was recovering from a gallbladder condition, said the exemptions ignored the intent of Congress to provide women with comprehensive coverage through the ACA.

“The glaring feature of what the government has done in expanding this exemption is to toss to the winds entirely Congress’s instruction that women need and shall have seamless, no-cost, comprehensive coverage,” she said during oral arguments. “This leaves the women to hunt for other government programs that might cover them, and for those who are not covered by Medicaid or one of the other government programs, they can get contraceptive coverage only from paying out of their own pocket, which is exactly what Congress didn’t want to happen.”

Associate Justice Samuel Alito Jr., meanwhile, indicated that a lower court opinion that had blocked the exemptions from going forward conflicts with the Supreme Court’s ruling in a related case, Burwell v. Hobby Lobby.

“Explain to me why the Third Circuit’s analysis of the question of substantial burden is not squarely inconsistent with our reasoning in Hobby Lobby,” Associate Justice Alito said during oral arguments. “Hobby Lobby held that, if a person sincerely believes that it is immoral to perform an act that has the effect of enabling another person to commit an immoral act, a federal court does not have the right to say that this person is wrong on the question of moral complicity. That’s precisely the situation here. Reading the Third Circuit’s discussion of the substantial burden question, I wondered whether they had read that part of the Hobby Lobby decision.”

The dispute surrounding the ACA’s birth control mandate and the extent of exemptions afforded has gone on for a decade and has led to numerous legal challenges. The ACA initially required all employers to cover birth control for employees with no copayments, but exempted group health plans of religious employers. Those religious employers were primarily churches and other houses of worship. After a number of complaints and lawsuits, the Obama administration created a workaround for nonprofit religious employers not included in that exemption to opt out of the mandate. However, critics argued the process itself was a violation of their religious freedom.

The issue led to the case of Zubik v. Burwell, a legal challenge over the mandate exemption that went before the U.S. Supreme Court in March 2016. The issue was never resolved however, and in May 2016, the Supreme Court vacated the lower court rulings related to Zubik v. Burwell and remanded the case back to the four appeals courts that had originally ruled on the issue.

In 2018, the Trump administration announced new rules aimed at broadening exemptions to the ACA’s contraceptive mandate to entities that object to services covered by the mandate on the basis of “sincerely held religious beliefs.” A second rule allowed nonprofit organizations and small businesses that had nonreligious moral convictions against the mandate to opt out.

Thirteen states and the District of Columbia then sued the Trump administration over the rules, as well as Pennsylvania and New Jersey in a separate case. Little Sisters of the Poor, a religious nonprofit operating a home in Pittsburgh, intervened in the case as an aggrieved party. An appeal court temporarily barred the regulations from moving forward.

During oral arguments, Solicitor General for the Department of Justice Noel J. Francisco said the exemptions are lawful because they are authorized under a provision of the ACA as well as the Religious Freedom Restoration Act (RFRA).

“RFRA at the very least authorizes the religious exemption,” Mr. Francisco said during oral arguments.

Chief Deputy Attorney General for Pennsylvania Michael J. Fischer argued that the Trump administration’s moral and religious exemption rules rest on overly broad assertions of agency authority.

“First, the agencies twist a narrow delegation that allows the Health Resources and Services Administration to decide which preventive services insurers must cover under the Women’s Health Amendment into a grant of authority so broad it allows them to permit virtually any employer or college to opt out of providing contraceptive coverage entirely, including for reasons as amorphous as vaguely defined moral beliefs,” he said during oral arguments. “Second, the agencies claim that RFRA, a statute that limits government action, affirmatively authorizes them to permit employers to deny women their rights to contraceptive coverage even in the absence of a RFRA violation in the first place.”

agallegos@mdedge.com

U.S. Supreme Court justices appear divided over whether the Trump administration acted properly when it expanded exemptions under the Affordable Care Act’s contraception mandate.

jsmith/iStockphoto

During oral arguments on May 6, the court expressed differing perspectives about the administration’s authority to allow for more exemptions under the health law’s birth control mandate and whether the expansions were reasonable. Justices heard the consolidated cases – Little Sisters of the Poor v. Pennsylvania and Trump v. Pennsylvania – by teleconference because of the COVID-19 pandemic. They are expected to make a decision by the summer.

Associate justice Ruth Bader Ginsburg, who participated in the telephone conference call from a hospital where she was recovering from a gallbladder condition, said the exemptions ignored the intent of Congress to provide women with comprehensive coverage through the ACA.

“The glaring feature of what the government has done in expanding this exemption is to toss to the winds entirely Congress’s instruction that women need and shall have seamless, no-cost, comprehensive coverage,” she said during oral arguments. “This leaves the women to hunt for other government programs that might cover them, and for those who are not covered by Medicaid or one of the other government programs, they can get contraceptive coverage only from paying out of their own pocket, which is exactly what Congress didn’t want to happen.”

Associate Justice Samuel Alito Jr., meanwhile, indicated that a lower court opinion that had blocked the exemptions from going forward conflicts with the Supreme Court’s ruling in a related case, Burwell v. Hobby Lobby.

“Explain to me why the Third Circuit’s analysis of the question of substantial burden is not squarely inconsistent with our reasoning in Hobby Lobby,” Associate Justice Alito said during oral arguments. “Hobby Lobby held that, if a person sincerely believes that it is immoral to perform an act that has the effect of enabling another person to commit an immoral act, a federal court does not have the right to say that this person is wrong on the question of moral complicity. That’s precisely the situation here. Reading the Third Circuit’s discussion of the substantial burden question, I wondered whether they had read that part of the Hobby Lobby decision.”

The dispute surrounding the ACA’s birth control mandate and the extent of exemptions afforded has gone on for a decade and has led to numerous legal challenges. The ACA initially required all employers to cover birth control for employees with no copayments, but exempted group health plans of religious employers. Those religious employers were primarily churches and other houses of worship. After a number of complaints and lawsuits, the Obama administration created a workaround for nonprofit religious employers not included in that exemption to opt out of the mandate. However, critics argued the process itself was a violation of their religious freedom.

The issue led to the case of Zubik v. Burwell, a legal challenge over the mandate exemption that went before the U.S. Supreme Court in March 2016. The issue was never resolved however, and in May 2016, the Supreme Court vacated the lower court rulings related to Zubik v. Burwell and remanded the case back to the four appeals courts that had originally ruled on the issue.

In 2018, the Trump administration announced new rules aimed at broadening exemptions to the ACA’s contraceptive mandate to entities that object to services covered by the mandate on the basis of “sincerely held religious beliefs.” A second rule allowed nonprofit organizations and small businesses that had nonreligious moral convictions against the mandate to opt out.

Thirteen states and the District of Columbia then sued the Trump administration over the rules, as well as Pennsylvania and New Jersey in a separate case. Little Sisters of the Poor, a religious nonprofit operating a home in Pittsburgh, intervened in the case as an aggrieved party. An appeal court temporarily barred the regulations from moving forward.

During oral arguments, Solicitor General for the Department of Justice Noel J. Francisco said the exemptions are lawful because they are authorized under a provision of the ACA as well as the Religious Freedom Restoration Act (RFRA).

“RFRA at the very least authorizes the religious exemption,” Mr. Francisco said during oral arguments.

Chief Deputy Attorney General for Pennsylvania Michael J. Fischer argued that the Trump administration’s moral and religious exemption rules rest on overly broad assertions of agency authority.

“First, the agencies twist a narrow delegation that allows the Health Resources and Services Administration to decide which preventive services insurers must cover under the Women’s Health Amendment into a grant of authority so broad it allows them to permit virtually any employer or college to opt out of providing contraceptive coverage entirely, including for reasons as amorphous as vaguely defined moral beliefs,” he said during oral arguments. “Second, the agencies claim that RFRA, a statute that limits government action, affirmatively authorizes them to permit employers to deny women their rights to contraceptive coverage even in the absence of a RFRA violation in the first place.”

agallegos@mdedge.com

U.S. Supreme Court justices appear divided over whether the Trump administration acted properly when it expanded exemptions under the Affordable Care Act’s contraception mandate.

jsmith/iStockphoto

During oral arguments on May 6, the court expressed differing perspectives about the administration’s authority to allow for more exemptions under the health law’s birth control mandate and whether the expansions were reasonable. Justices heard the consolidated cases – Little Sisters of the Poor v. Pennsylvania and Trump v. Pennsylvania – by teleconference because of the COVID-19 pandemic. They are expected to make a decision by the summer.

Associate justice Ruth Bader Ginsburg, who participated in the telephone conference call from a hospital where she was recovering from a gallbladder condition, said the exemptions ignored the intent of Congress to provide women with comprehensive coverage through the ACA.

“The glaring feature of what the government has done in expanding this exemption is to toss to the winds entirely Congress’s instruction that women need and shall have seamless, no-cost, comprehensive coverage,” she said during oral arguments. “This leaves the women to hunt for other government programs that might cover them, and for those who are not covered by Medicaid or one of the other government programs, they can get contraceptive coverage only from paying out of their own pocket, which is exactly what Congress didn’t want to happen.”

Associate Justice Samuel Alito Jr., meanwhile, indicated that a lower court opinion that had blocked the exemptions from going forward conflicts with the Supreme Court’s ruling in a related case, Burwell v. Hobby Lobby.

“Explain to me why the Third Circuit’s analysis of the question of substantial burden is not squarely inconsistent with our reasoning in Hobby Lobby,” Associate Justice Alito said during oral arguments. “Hobby Lobby held that, if a person sincerely believes that it is immoral to perform an act that has the effect of enabling another person to commit an immoral act, a federal court does not have the right to say that this person is wrong on the question of moral complicity. That’s precisely the situation here. Reading the Third Circuit’s discussion of the substantial burden question, I wondered whether they had read that part of the Hobby Lobby decision.”

The dispute surrounding the ACA’s birth control mandate and the extent of exemptions afforded has gone on for a decade and has led to numerous legal challenges. The ACA initially required all employers to cover birth control for employees with no copayments, but exempted group health plans of religious employers. Those religious employers were primarily churches and other houses of worship. After a number of complaints and lawsuits, the Obama administration created a workaround for nonprofit religious employers not included in that exemption to opt out of the mandate. However, critics argued the process itself was a violation of their religious freedom.

The issue led to the case of Zubik v. Burwell, a legal challenge over the mandate exemption that went before the U.S. Supreme Court in March 2016. The issue was never resolved however, and in May 2016, the Supreme Court vacated the lower court rulings related to Zubik v. Burwell and remanded the case back to the four appeals courts that had originally ruled on the issue.

In 2018, the Trump administration announced new rules aimed at broadening exemptions to the ACA’s contraceptive mandate to entities that object to services covered by the mandate on the basis of “sincerely held religious beliefs.” A second rule allowed nonprofit organizations and small businesses that had nonreligious moral convictions against the mandate to opt out.

Thirteen states and the District of Columbia then sued the Trump administration over the rules, as well as Pennsylvania and New Jersey in a separate case. Little Sisters of the Poor, a religious nonprofit operating a home in Pittsburgh, intervened in the case as an aggrieved party. An appeal court temporarily barred the regulations from moving forward.

During oral arguments, Solicitor General for the Department of Justice Noel J. Francisco said the exemptions are lawful because they are authorized under a provision of the ACA as well as the Religious Freedom Restoration Act (RFRA).

“RFRA at the very least authorizes the religious exemption,” Mr. Francisco said during oral arguments.

Chief Deputy Attorney General for Pennsylvania Michael J. Fischer argued that the Trump administration’s moral and religious exemption rules rest on overly broad assertions of agency authority.

“First, the agencies twist a narrow delegation that allows the Health Resources and Services Administration to decide which preventive services insurers must cover under the Women’s Health Amendment into a grant of authority so broad it allows them to permit virtually any employer or college to opt out of providing contraceptive coverage entirely, including for reasons as amorphous as vaguely defined moral beliefs,” he said during oral arguments. “Second, the agencies claim that RFRA, a statute that limits government action, affirmatively authorizes them to permit employers to deny women their rights to contraceptive coverage even in the absence of a RFRA violation in the first place.”

agallegos@mdedge.com

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

A triple-antiviral therapy regimen of interferon-beta1, lopinavir/ritonavir, and ribavirin shortened median time to COVID-19 viral negativity by 5 days in a small trial from Hong Kong.

Courtesy NIAID-RML

In an open-label, randomized phase 2 trial in patients with mild or moderate COVID-19 infections, the median time to viral negativity by nasopharyngeal swab was 7 days for 86 patients assigned to receive a 14-day course of lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million international units of interferon beta-1b on alternate days, compared with a median time to negativity of 12 days for patients treated with lopinavir/ritonavir alone (P = .0010), wrote Ivan Fan-Ngai Hung, MD, from Gleaneagles Hospital in Hong Kong, and colleagues.

“Triple-antiviral therapy with interferon beta-1b, lopinavir/ritonavir, and ribavirin were safe and superior to lopinavir/ritonavir alone in shortening virus shedding, alleviating symptoms, and facilitating discharge of patients with mild to moderate COVID-19,” they wrote in a study published online in The Lancet.

Patients who received the combination also had significantly shorter time to complete alleviation of symptoms as assessed by a National Early Warning Score 2 (NEWS2, a system for detecting clinical deterioration in patients with acute illnesses) score of 0 (4 vs. 8 days, respectively; hazard ratio 3.92, P < .0001), and to a Sequential Organ Failure Assessment (SOFA) score of 0 (3 vs. 8 days, HR 1.89, P = .041).

The median hospital stay was 9 days for patients treated with the combination, compared with 14.5 days for controls (HR 2.72, P = .016).

In most patients treated with the combination, SARS-CoV-2 viral load was effectively suppressed in all clinical specimens, including nasopharyngeal swabs, throat and posterior oropharyngeal saliva, and stool.

In addition, serum levels of interleukin 6 (IL-6) – an inflammatory cytokine implicated in the cytokine storm frequently seen in patients with severe COVID-19 infections – were significantly lower on treatment days 2, 6, and 8 in patients treated with the combination, compared with those treated with lopinavir/ritonavir alone.

“Our trial demonstrates that early treatment of mild to moderate COVID-19 with a triple combination of antiviral drugs may rapidly suppress the amount of virus in a patient’s body, relieve symptoms, and reduce the risk to health care workers by reducing the duration and quantity of viral shedding (when the virus is detectable and potentially transmissible). Furthermore, the treatment combination appeared safe and well tolerated by patients,” said lead investigator Professor Kwok-Yung Yuen from the University of Hong Kong, in a statement.

“Despite these encouraging findings,” he continued, “we must confirm in larger phase 3 trials that interferon beta-1b alone or in combination with other drugs is effective in patients with more severe illness (in whom the virus has had more time to replicate).”

Plausible rationale

Benjamin Medoff, MD, chief of the division of pulmonary and critical care medicine at Massachusetts General Hospital in Boston, who was not involved in the study, said in an interview that the biologic rationale for the combination is plausible.

“I think this is a promising study that suggests that a regimen of interferon beta-1b, lopinavir/ritonavir, and ribavirin can shorten the duration of infection and improve symptoms in COVID-19 patients especially if started early in disease, in less than 7 days of symptom onset,” he said in reply to a request for expert analysis.

“The open-label nature and small size of the study limits the broad use of the regimen as noted by the authors, and it’s important to emphasize that the subjects enrolled did not have very severe disease (not in the ICU). However, the study does suggest that a larger truly randomized study is warranted,” he said.

AIDS drugs repurposed

Lopinavir/ritonavir is commonly used to treat HIV/AIDS throughout the world, and the investigators had previously reported that the antiviral agents combined with ribavirin reduced deaths and the need for intensive ventilator support among patients with SARS-CoV, the betacoronavirus that causes severe acute respiratory syndrome (SARS), and antivirals have shown in vitro activity against both SARS-CoV and MERS-CoV, the closely related pathogen that causes Middle East respiratory syndrome.

“ However the viral load of SARS and MERS peaks at around day 7-10 after symptom onset, whereas the viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single-drug treatments in this setting of patients with a high viral load at presentation,” the investigators wrote.

To test this, they enrolled adults patients admitted to one of six Hong Kong Hospitals for virologically confirmed COVID-19 infections from Feb. 10 through March 20, 2020.

A total of 86 patients were randomly assigned to the combination and 41 to lopinavir/ritonavir alone as controls, at doses described above.

Patients who entered the trial within less than 7 days of symptom onset received the triple combination, with interferon dosing adjusted according to the day that treatment started. Patients recruited 1 or 2 days after symptom onset received three doses of interferon, patients started on day 3 or 4 received two doses, and those started on days 5 or 6 received one interferon dose. Patients recruited 7 days or later from symptom onset did not receive interferon beta-1b because of its proinflammatory effects.

In post-hoc analysis by day of treatment initiation, clinical and virological outcomes (except stool samples) were superior in patients admitted less than 7 days after symptom onset for the 52 patients who received a least one interferon dose plus lopinavir/ritonavir and ribavirin, compared with 24 patients randomized to the control arm (lopinavir/ritonavir only). In contrast, among patients admitted and started on treatment at day 7 or later after symptom onset, there were no differences between those who received lopinavir/ritonavir alone or combined with ribavirin.

Adverse events were reported in 41 of 86 patients in the combination group and 20 of 41 patients in the control arm. The most common adverse events were diarrhea, occurring in 52 of all 127 patients, fever in 48, nausea in 43, and elevated alanine transaminase level in 18. The side effects generally resolved within 3 days of the start of treatments.

There were no serious adverse events reported in the combination group. One patient in the control group had impaired hepatic enzymes requiring discontinuation of treatment. No patients died during the study.

The study was funded by the Shaw Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine. The authors and Dr. Medoff declared no competing interests.

SOURCE: Hung IFN et al. Lancet. 2020 May 8. doi: 10.1016/S0140-6736(20)31101-6.

Photo-manipulated selfies can provide adolescents an influential window into the wrinkled, sun-damaged future that may be theirs if they’re not careful, a new study suggests.

In the study, researchers found that Brazilian teenagers, especially girls, were more likely to protect themselves from the sun if they got glimpses of how sun exposure could damage their faces. “The intervention used in this study was effective in convincing a substantial part of the students to take up regular sunscreen use and to examine their own skin regularly,” they wrote. “Moreover, these effects were maintained for at least half a year.”

The study, led by Titus J. Brinker, MD, of the department of dermatology, in the National Center for Tumor Diseases, German Cancer Research Center in Heidelberg, Germany, appeared online on May 6 in JAMA Dermatology (2020 May 6. doi: 10.1001/jamadermatol.2020.0511.

Dr. Brinker and colleagues launched the study in 2018 at eight public schools that serve grades 9-12 in Itaúna, a city in southeast Brazil, randomly assigning 1,573 students (52% girls, 48% boys; mean age, 16 years) to the intervention or control group.

Those in the intervention group attended seminars in which medical students showed them selfies of their classmates altered with a mobile phone app called Sunface, developed by Dr. Brinker. The free app examines photographs of faces and adds wrinkles, spots, precancerous lesions, and other signs of damage to them based on different levels of sun exposure over 5-25 years.

The app, which takes the skin types of the subjects into account, was described by the Vice news site as “terrifying” in a 2018 article. It “could very well scare you into using sunscreen and wearing hats,” the author of that article wrote.

The app appeared to do just that – but not universally, according to the new study.

At 6 months, there was no change in sun protection habits in the control group. But among those remaining in the intervention group, the use of daily sunscreen significantly increased from 15% (110 of 734 students) during the 30 days prior to the survey, to 23% (139 of 607 students) at the 6-month follow-up (P less than .001), as did the percentage of those who performed at least one skin self-examination within the 6 months (25% to 49%; P less than .001). The students were slightly less likely to use tanning beds within the previous month (19% to 15%; P = .04); the researchers speculate that it’s easier to gain a new healthy habit than get rid of an old unhealthy one.

Girls were much more likely to change their habits than boys. The number needed to treat to reach the primary endpoint, daily sunscreen use, was 8 for girls and 31 for boys.

The researchers noted that the dropout rate was higher in the intervention group (17%) vs. the control group (6%). “The intervention may have led to strong adverse reactions in some students, leading to the observed higher dropout rate in the intervention group,” they wrote. Changes to the way the app is used could improve the dropout rate, but potentially hurt the intervention’s impact, they added.

In an accompanying editorial in JAMA Dermatology, two health intervention researchers wrote that “this work represents a needed shift toward scalable interventions that bring messaging to target populations using their preferred technology” (2020 May 6. doi: 10.1001/jamadermatol.2020.0510).

Referring to the finding that sunscreen use did not change much among the boys in the study, the authors, Sherry L. Pagoto, PhD, of the Institute for Collaborations on Health, Interventions, and Policy at the University of Connecticut, Storrs, and Alan C. Geller, MPH, RN, of the Harvard TH Chan School of Public Health, Boston, also noted that “teen boys have been largely resistant to traditional and nontraditional forms of sun safety education.”

“Teasing out sex differences is important,” they added, “because sun protection interventions woven into existing programs at pools, beaches, and sporting events might be more appealing and enduring for boys, particularly if the technology they regularly use is leveraged.”

Dr. Brinker disclosed receiving an award from La Fondation la Roche-Posay, which also provided support for the study which partially funded the study, for his research on the Sunface app. The University of Itaúna provided other study funding. Several other study authors had various disclosures. Dr. Pagoto disclosed consulting work and personal fees from Johnson & Johnson, unrelated to the topic of the commentary; Dr. Geller had no disclosures.

SOURCES: Brinker TJ et al. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0511; Pagoto SL and Geller AC. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0510.

Photo-manipulated selfies can provide adolescents an influential window into the wrinkled, sun-damaged future that may be theirs if they’re not careful, a new study suggests.

In the study, researchers found that Brazilian teenagers, especially girls, were more likely to protect themselves from the sun if they got glimpses of how sun exposure could damage their faces. “The intervention used in this study was effective in convincing a substantial part of the students to take up regular sunscreen use and to examine their own skin regularly,” they wrote. “Moreover, these effects were maintained for at least half a year.”

The study, led by Titus J. Brinker, MD, of the department of dermatology, in the National Center for Tumor Diseases, German Cancer Research Center in Heidelberg, Germany, appeared online on May 6 in JAMA Dermatology (2020 May 6. doi: 10.1001/jamadermatol.2020.0511.

Dr. Brinker and colleagues launched the study in 2018 at eight public schools that serve grades 9-12 in Itaúna, a city in southeast Brazil, randomly assigning 1,573 students (52% girls, 48% boys; mean age, 16 years) to the intervention or control group.

Those in the intervention group attended seminars in which medical students showed them selfies of their classmates altered with a mobile phone app called Sunface, developed by Dr. Brinker. The free app examines photographs of faces and adds wrinkles, spots, precancerous lesions, and other signs of damage to them based on different levels of sun exposure over 5-25 years.

The app, which takes the skin types of the subjects into account, was described by the Vice news site as “terrifying” in a 2018 article. It “could very well scare you into using sunscreen and wearing hats,” the author of that article wrote.

The app appeared to do just that – but not universally, according to the new study.

At 6 months, there was no change in sun protection habits in the control group. But among those remaining in the intervention group, the use of daily sunscreen significantly increased from 15% (110 of 734 students) during the 30 days prior to the survey, to 23% (139 of 607 students) at the 6-month follow-up (P less than .001), as did the percentage of those who performed at least one skin self-examination within the 6 months (25% to 49%; P less than .001). The students were slightly less likely to use tanning beds within the previous month (19% to 15%; P = .04); the researchers speculate that it’s easier to gain a new healthy habit than get rid of an old unhealthy one.

Girls were much more likely to change their habits than boys. The number needed to treat to reach the primary endpoint, daily sunscreen use, was 8 for girls and 31 for boys.

The researchers noted that the dropout rate was higher in the intervention group (17%) vs. the control group (6%). “The intervention may have led to strong adverse reactions in some students, leading to the observed higher dropout rate in the intervention group,” they wrote. Changes to the way the app is used could improve the dropout rate, but potentially hurt the intervention’s impact, they added.

In an accompanying editorial in JAMA Dermatology, two health intervention researchers wrote that “this work represents a needed shift toward scalable interventions that bring messaging to target populations using their preferred technology” (2020 May 6. doi: 10.1001/jamadermatol.2020.0510).

Referring to the finding that sunscreen use did not change much among the boys in the study, the authors, Sherry L. Pagoto, PhD, of the Institute for Collaborations on Health, Interventions, and Policy at the University of Connecticut, Storrs, and Alan C. Geller, MPH, RN, of the Harvard TH Chan School of Public Health, Boston, also noted that “teen boys have been largely resistant to traditional and nontraditional forms of sun safety education.”

“Teasing out sex differences is important,” they added, “because sun protection interventions woven into existing programs at pools, beaches, and sporting events might be more appealing and enduring for boys, particularly if the technology they regularly use is leveraged.”

Dr. Brinker disclosed receiving an award from La Fondation la Roche-Posay, which also provided support for the study which partially funded the study, for his research on the Sunface app. The University of Itaúna provided other study funding. Several other study authors had various disclosures. Dr. Pagoto disclosed consulting work and personal fees from Johnson & Johnson, unrelated to the topic of the commentary; Dr. Geller had no disclosures.

SOURCES: Brinker TJ et al. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0511; Pagoto SL and Geller AC. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0510.

Photo-manipulated selfies can provide adolescents an influential window into the wrinkled, sun-damaged future that may be theirs if they’re not careful, a new study suggests.

In the study, researchers found that Brazilian teenagers, especially girls, were more likely to protect themselves from the sun if they got glimpses of how sun exposure could damage their faces. “The intervention used in this study was effective in convincing a substantial part of the students to take up regular sunscreen use and to examine their own skin regularly,” they wrote. “Moreover, these effects were maintained for at least half a year.”

The study, led by Titus J. Brinker, MD, of the department of dermatology, in the National Center for Tumor Diseases, German Cancer Research Center in Heidelberg, Germany, appeared online on May 6 in JAMA Dermatology (2020 May 6. doi: 10.1001/jamadermatol.2020.0511.

Dr. Brinker and colleagues launched the study in 2018 at eight public schools that serve grades 9-12 in Itaúna, a city in southeast Brazil, randomly assigning 1,573 students (52% girls, 48% boys; mean age, 16 years) to the intervention or control group.

Those in the intervention group attended seminars in which medical students showed them selfies of their classmates altered with a mobile phone app called Sunface, developed by Dr. Brinker. The free app examines photographs of faces and adds wrinkles, spots, precancerous lesions, and other signs of damage to them based on different levels of sun exposure over 5-25 years.

The app, which takes the skin types of the subjects into account, was described by the Vice news site as “terrifying” in a 2018 article. It “could very well scare you into using sunscreen and wearing hats,” the author of that article wrote.

The app appeared to do just that – but not universally, according to the new study.

At 6 months, there was no change in sun protection habits in the control group. But among those remaining in the intervention group, the use of daily sunscreen significantly increased from 15% (110 of 734 students) during the 30 days prior to the survey, to 23% (139 of 607 students) at the 6-month follow-up (P less than .001), as did the percentage of those who performed at least one skin self-examination within the 6 months (25% to 49%; P less than .001). The students were slightly less likely to use tanning beds within the previous month (19% to 15%; P = .04); the researchers speculate that it’s easier to gain a new healthy habit than get rid of an old unhealthy one.

Girls were much more likely to change their habits than boys. The number needed to treat to reach the primary endpoint, daily sunscreen use, was 8 for girls and 31 for boys.

The researchers noted that the dropout rate was higher in the intervention group (17%) vs. the control group (6%). “The intervention may have led to strong adverse reactions in some students, leading to the observed higher dropout rate in the intervention group,” they wrote. Changes to the way the app is used could improve the dropout rate, but potentially hurt the intervention’s impact, they added.

In an accompanying editorial in JAMA Dermatology, two health intervention researchers wrote that “this work represents a needed shift toward scalable interventions that bring messaging to target populations using their preferred technology” (2020 May 6. doi: 10.1001/jamadermatol.2020.0510).

Referring to the finding that sunscreen use did not change much among the boys in the study, the authors, Sherry L. Pagoto, PhD, of the Institute for Collaborations on Health, Interventions, and Policy at the University of Connecticut, Storrs, and Alan C. Geller, MPH, RN, of the Harvard TH Chan School of Public Health, Boston, also noted that “teen boys have been largely resistant to traditional and nontraditional forms of sun safety education.”

“Teasing out sex differences is important,” they added, “because sun protection interventions woven into existing programs at pools, beaches, and sporting events might be more appealing and enduring for boys, particularly if the technology they regularly use is leveraged.”

Dr. Brinker disclosed receiving an award from La Fondation la Roche-Posay, which also provided support for the study which partially funded the study, for his research on the Sunface app. The University of Itaúna provided other study funding. Several other study authors had various disclosures. Dr. Pagoto disclosed consulting work and personal fees from Johnson & Johnson, unrelated to the topic of the commentary; Dr. Geller had no disclosures.

SOURCES: Brinker TJ et al. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0511; Pagoto SL and Geller AC. JAMA Dermatol. 2020 May 6. doi: 10.1001/jamadermatol.2020.0510.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

 

 

The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

 

 

Injection technique: Consider these helpful tips

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; kd6fp@viginia.edu.

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

 

 

The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

 

 

Injection technique: Consider these helpful tips

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; kd6fp@viginia.edu.

In-office procedures are increasingly emphasized as a way to reduce referrals, avoid treatment delay, and increase practice revenue. Local analgesia is administered before many in-office procedures such as biopsies, toenail removal, and laceration repair. Skin procedures are performed most commonly; nearly three-quarters (74%) of family physicians (FPs) provided these services in 2018.¹ Administration of local anesthetic is often the most feared and uncomfortable step in the entire process.²

Knowledge of strategies to reduce pain associated with anesthetic administration can make a huge difference in the patient experience. This article explores evidence-based techniques for administering a local anesthetic with minimal patient discomfort.

4 factors influence the painof local anesthetic administration

Pain is perceived during the administration of local anesthetic because of the insertion of the needle and the increased pressure from the injection of fluid. The needle causes sharp, pricking “first pain” via large diameter, myelinated A-delta fibers, and the fluid induces unmyelinated C-fiber activation via tissue distention resulting in dull, diffuse “second pain.”

Four factors influence the experience of pain during administration of local anesthetic: the pharmacologic properties of the anesthetic itself, the equipment used, the environment, and the injection technique. Optimizing all 4 factors limits patient discomfort.

Pharmacologic agents: Lidocaine is often the agent of choice

Local anesthetics differ in maximal dosing, onset of action, and duration of effect (TABLE³). Given its ubiquity in clinics and hospitals, 1% lidocaine is often the agent of choice. Onset of effect occurs within minutes and lasts up to 2 hours. Alternative agents, such as bupivacaine or ropivacaine, may be considered to prolong the anesthetic effect; however, limited evidence exists to support their use in office-based procedures. Additionally, bupivacaine and ropivacaine may be associated with greater pain on injection and parasthesias lasting longer than the duration of pain control.^4-6 In practice, maximal dosing is most important in the pediatric population, given the smaller size of the patients and their increased susceptibility to toxicity.

Calculating the maximum recommended dose. To calculate the maximum recommended dose of local anesthetic, you need to know the concentration of the anesthetic, the maximum allowable dose (mg/kg), and the weight of the patient.^7,8 The concentration of the local anesthetic is converted from percentage to weight per unit volume (eg, 1% = 10 mg/mL; 0.5% = 5 mg/mL). Multiply the patient's weight (kg) by the maximum dose of local anesthetic (mg/kg) and divide by the concentration of the local anesthetic (mg/mL) to get the maximum recommended dose in milliliters. Walsh et al⁹ described a simplified formula to calculate the maximum allowable volume of local anesthetics in milliliters:

(maximum allowable dose in mg/kg) × (weight in kg) × (1 divided by the concentration of anesthetic).

For delivery of lidocaine with epinephrine in a 50-lb (22.7-kg) child, the calculation would be (7 mg/kg) × (22.7 kg) × (1 divided by 10 mg/mL) = 15.9 mL.

Continue to: The advantages (and misconceptions) of epinephrine

 

 

The advantages (and misconceptions) of epinephrine

The advantage of adding epinephrine is that it prolongs the effect of the anesthesia and it decreases bleeding. Epinephrine is commonly available as a premixed solution with lidocaine or bupivacaine at a concentration of 1:100,000 and is generally differentiated from “plain” local anesthetic by a red label and cap. Although maximum vasoconstriction may occur as long as 30 minutes after injection,¹⁰ adequate vasoconstriction is achieved in 7 to 10 minutes for excision of skin lesions.¹¹

Traditional teaching recommends against using epinephrine in the “fingers, toes, penis, ears, or nose” because of potential arterial spasm, ischemia, and gangrene distal to the injection site.¹² These concerns were based on experiences with procaine and cocaine mixed with epinephrine. Studies suffered from multiple confounders, including tourniquets and nonstandardized epinephrine concentrations.^13-15

Add epinephrine to the anesthetic solution to prolong anesthesia and decrease bleeding.

No association of distal ischemia with epinephrine use was identified in a recent Cochrane Review or in another multicenter prospective study.^16,17 Phentolamine, a non-selective alpha-adrenergic receptor antagonist and vasodilator, can be administered to reverse vasoconstriction following inadvertent administration of high-dose epinephrine (1:1000) via anaphylaxis autoinjector kits.

Dosing of phentolamine is 1 mL of 1 mg/mL solution delivered subcutaneously to the affected area; reversal decreases the duration of vasoconstriction from 320 minutes to approximately 85 minutes.¹⁸ As always, when applying literature to clinical practice, one must keep in mind the risks and benefits of any intervention. As such, in patients with pre-existing vascular disease, vaso-occlusive or vasospastic disease, or compromised perfusion due to trauma, one must weigh the benefits of the hemostatic effect against potential ischemia of already susceptible tissues. In such instances, omitting epinephrine from the solution is reasonable.

The benefits of sodium bicarbonate

The acidity of the solution contributes to the level of pain associated with administration of local anesthesia. Previously opened containers become more acidic.¹⁹ Addition of 8.4% sodium bicarbonate, at a ratio of 1 mL per 10 mL of 1% lidocaine with 1:100,000 epinephrine, neutralizes the pH to 7.4.¹⁹ A Cochrane Review showed that correction of pH to physiologic levels results in a significant reduction in pain.²⁰

Continue to: This solution can be...

This solution can be easily prepared, as standard syringes hold an additional milliliter (ie, 10-mL syringes hold 11 mL) and, thus, can accommodate the additional volume of bicarbonate.²¹

Warming the solution helps, too

Warming the solution to body temperature prior to injection decreases pain on injection.²² This may be done in a variety of ways depending on available in-office equipment. Water baths, incubators, fluid warmers, heating pads, or specific syringe warmers may be used. Multiple studies have shown improvement in patient satisfaction with warming.²³ Moreover, warming and buffering solution provide a synergistic effect on pain reduction.²³

Equipment: Size matters

Smaller diameter needles. Reducing the outer diameter of the needle used for injection improves pain by reducing activation of nociceptors.^24-26 Reduced inner diameter restricts injection speed, which further reduces pain.²⁵ We recommend 27- to 30-gauge needles for subcutaneous injection and 25- to 27-gauge needles for intra-articular or tendon sheath injections.

Appropriate syringe size. Filling a syringe to capacity results in maximal deployment of the plunger. This requires greater handspan, which can lead to fatigue and loss of control during injection.^26,27 Using a syringe filled to approximately half its capacity results in improved dexterity. We recommend 10-mL syringes with 5 mL to 6 mL of local anesthetic for small procedures and 20-mL syringes filled with 10 mL to 12 mL for larger procedures.

Topical local anesthetics may be used either as an adjunct to decrease pain during injection or as the primary anesthetic.²⁸ A variety of agents are available for clinical use, including eutectic mixture of local anesthetics (EMLA), lidocaine-epinephrine-tetracaine (LET), lidocaine, benzocaine, and tetracaine. FPs should be familiar with their different pharmacokinetic profiles.

Continue to: EMLA is a mixture of...

EMLA is a mixture of 25 mg/mL of lidocaine and 25 mg/mL of prilocaine. It is indicated for topical anesthesia on intact, nonmucosal, uninjured skin (maximal dose 20 g/200 cm² of surface area). It is applied in a thick layer and covered with an occlusive dressing (eg, Tegaderm) to enhance dermal penetration. The depth of penetration increases with application time and may reach a maximum depth of 3 mm and 5 mm following 60-minute and 120-minute application times, respectively.²⁸ Duration of effect is 60 to 120 minutes.

LET, which is a mixture of 4% lidocaine, 0.1% epinephrine, and 0.5% tetracaine, may be used on nonintact, nonmucosal surfaces. Typically, 1 mL to 5 mL of gel is applied directly to the target area and is followed by application of direct pressure for 15 to 30 minutes. LET is not effective on intact skin and is contraindicated in children < 2 years of age.²⁸

Cooling sprays or ice. Topical skin refrigerants, or vapocoolants (eg, ethyl chloride spray), offer an option for short-term local anesthesia that is noninvasive and quick acting. Ethyl chloride is a gaseous substance that extracts heat as it evaporates from the skin, resulting in a transient local conduction block. Skin refrigerants are an option to consider for short procedures such as intra-articular injections, venipuncture, or skin tag excision, or as an adjunct prior to local anesthetic delivery.^29-32 Research has shown that topical ethyl chloride spray also possesses antiseptic properties.^29,33

Environment: Make a few simple changes

Direct observation of needle penetration is associated with increased pain; advising patients to avert their gaze will mitigate the perception of pain.³⁴ Additionally, research has shown that creating a low-anxiety environment improves patient-reported outcomes in both children and adults.³⁵ Music or audiovisual or multimedia aids, for example, decrease pain and anxiety, particularly among children, and can be readily accessed with smart devices.^36-39

Warming and buffering solution provide a synergistic effect on pain reduction.

We also recommend avoiding terms such as “pinch,” “bee sting,” or “stick” in order to reduce patient anxiety. Instead, we use language such as, “This is the medicine that will numb the area so you will be comfortable during the procedure.”⁴⁰

Continue to: Injection technique

 

 

Injection technique: Consider these helpful tips

Site of needle entry. Prior to injecting local anesthesia, assess the area where the procedure is planned (FIGURE 1). The initial injection site should be proximal along the path of innervation. If regional nerves are anesthetized proximally and infiltration of local anesthesia proceeds distally, the initial puncture will be painful; however, further injections will be through anesthetized skin. Additionally, consider and avoid regional vascular anatomy.^41,42

Counter-stimulation. Applying firm pressure, massaging, or stroking the site prior to or during the injection decreases pain.^43,44 This technique may be performed by firmly pinching the area of planned injection between the thumb and index fingers, inserting the needle into the pinched skin, and maintaining pressure on the area until the anesthetic effect is achieved.

Angle of needle insertion. Perpendicular entry of the needle into the skin appears to reduce injection site pain (FIGURE 1). Anecdotal reports are supported by a randomized, controlled crossover trial that demonstrated significantly reduced pain with perpendicular injection compared to delivery at 45°.⁴⁵

Depth of injection. Subcutaneous needle placement is associated with significantly less pain than injection into superficial dermis.^2,46 Dermal wheals cause distention of the dermis, increased intradermal pressure, and greater activation of pain afferents in comparison to injection in the subcutaneous space.⁴⁶ One important exception is the shave biopsy in which dermal distention is, in fact, desirable to ensure adequate specimen collection.

Other methods of pain reduction should still be employed. In the setting of traumatic wounds when a laceration is present, injection into the subcutaneous fat through the wound is easy and associated with less pain than injection through intact skin.⁴⁷

Continue to: Speed of injection

Speed of injection. Rapid injection of anesthesia is associated with worse injection site pain and decreased patient satisfaction.^48-50 Slowing the rate of injection causes less rapid distention of the dermis and subcutaneous space, resulting in decreased pain afferent activation and increased time for nerve blockade. Its importance is underscored by a prospective, randomized trial that compared rate of administration with buffering of local anesthetics and demonstrated that slow administration impacted patient-perceived pain more than buffering solution.⁵¹

Needle stabilization. Following perpendicular entry of the needle into the area of planned infiltration, deliver 0.5 mL of local anesthetic into the subcutaneous space without movement of the needle tip.⁵² With a stabilized needle tip, pain associated with initial needle entry is no longer perceived within 15 to 30 seconds.

Any reinsertion of the needle should be through previously anesthetized skin.

It is paramount to stabilize both the syringe and the area of infiltration to prevent patient movement from causing iatrogenic injury or the need for multiple needlesticks. This can be accomplished by maintaining the dominant hand in a position to inject (ie, thumb on the plunger).

Needle reinsertion. Once subcutaneous swelling of local anesthesia is obtained, the needle may be slowly advanced, maintaining a palpable subcutaneous wavefront of local anesthesia ahead of the needle tip as it moves proximally to distally.^2,52 Any reinsertion of the needle should be through previously anesthetized skin; this blockade is assessed by the presence of palpable tumescence and blanching (from the epinephrine effect).⁵³

An example of the application of these injection pearls is demonstrated in the ­administration of a digital nerve block in FIGURE 2.^54,55 With the use of the techniques outlined here, the patient ideally experiences only the initial needle entry and is comfortable for the remainder of the procedure.

PHOTO COURTESY OF BRENT DEGEORGE, MD, PhD, AND ROBERTO MARTINEZ, MD, THE UNIVERSITY OF VIRGINIA DEPARTMENT OF PLASTIC SURGERY

CORRESPONDENCE
Katharine C. DeGeorge, MD, MS, Department of Family Medicine, University of Virginia, 1215 Lee Street, Charlottesville, VA, 22903; kd6fp@viginia.edu.

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com