Article

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

Evidence summary

Small studies offer mixed evidence of benefit

Seven RCTs using manual therapies to treat chronic tension headaches have reported the change in headache frequency (TABLE^1-7). Most, but not all, manual therapies significantly improved headache frequency.

Participants ranged in age from 18 to 65 years, with mean age ranges of 33 to 42 years in each study. At baseline, patients had 10 or more tension-type headaches per month. The manual therapies varied in techniques, duration, and the training of the person performing the intervention:

• Twice-weekly chiropractic spinal manipulation for 6 weeks¹
• Soft-tissue therapy plus spinal manipulation (8 treatments over 4 weeks)²
• Chiropractic spinal manipulation with or without amitriptyline for 14 weeks³
• Corrective osteopathic manipulation treatment (OMT) techniques tailored for each patient for 1 month⁴
• High-velocity low-amplitude manipulation (HVLA) plus exercise or myofascial release plus exercise twice weekly for 8 weeks⁵
• Manual therapy treatment consisting of a combination of mobilizations of the cervical and thoracic spine, exercises, and postural correction for up to 9 sessions of 30 minutes each⁶
• One hour of direct or indirect myofascial release treatment twice weekly for 12 weeks.⁷

Three studies involved chiropractic providers.^1-3 One study (n = 19) found a positive effect, in which chiropractic manipulation augmented with amitriptyline performed better than chiropractic manipulation alone.³ Another chiropractic study did not find an immediate posttreatment benefit but did report significant headache reduction at the 4-week follow-up interval.¹ The third chiropractic study did not show additional benefit from HVLA manipulation.²

One small study involving osteopathic physicians using OMT found reduced headache frequency after 12 weeks but not at 4 weeks.⁴ Another study, comparing HVLA or myofascial release with exercise to exercise alone, found benefit for the HVLA group but not for myofascial release; interventions in this study were performed by a physician with at least 6 years of unspecified manual therapy experience.⁵ A small study of manual therapists found improvement at the end of manual therapy but not at 18 months.⁶ Another small study using providers with 10 months’ experience with myofascial release found reduced headache frequency 4 weeks after a course of direct and indirect myofascial release (compared with sham release).⁷

Editor’s takeaway

It isn’t hard to imagine why muscle tension headaches might respond to certain forms of manual therapy. However, all available studies of these modalities have been small (< 100 patients) or lacked blinding, introducing the potential for significant bias. Nevertheless, for now it appears reasonable to refer interested patients with tension headache to an osteopathic physician for OMT or myofascial release to reduce headache frequency.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

AN OTHERWISE HEALTHY 53-YEAR-OLD MAN presented with a 6-month history of an acneiform eruption on his face. There was no history of teenage acne or allergic contact dermatitis.

Scattered papules and pustules were present on the forehead, nose, and cheeks, with background erythema and telangiectasias (FIGURE 1). A few pinpoint crusted excoriations were noted. A sample was taken from the papules and pustules using a #15 blade and submitted for examination.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Under light microscopy, the scraping revealed Demodex mites (FIGURE 2). It has been proposed that these mites play a role in the inflammatory process seen in rosacea, although studies have yet to determine whether the inflammatory symptoms of rosacea cause the mites to proliferate or if the mites contribute to the initial inflammatory process.^1,2

Demodex folliculorum and D brevis are part of normal skin flora; they are found in about 12% of all follicles and most commonly involve the face.³ They often become abundant in the presence of numerous sebaceous glands. Men have more sebaceous glands than women do, and thus run a greater risk for infestation with mites. An abnormal proliferation of Demodex mites can lead to demodicosis.

A proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.

Demodex mites can be examined microscopically via the skin surface sampling technique known as scraping, which was done in this case. Samples taken from the papules and pustules utilizing a #15 blade are placed in immersion oil on a glass slide, cover-slipped, and examined by light microscopy.

Rosacea is thought to be an inflammatory disease in which the immune system is triggered by a variety of factors, including UV light, heat, stress, alcohol, hormonal influences, and microorganisms.^1,4 The disease is found in up to 10% of the population worldwide.¹

The diagnosis of rosacea requires at least 1 of the 2 “core features”—persistent central facial erythema or phymatous changes—or 2 of 4 “major features”: papules/pustules, ocular manifestation, flushing, and telangiectasias. There are 3 phenotypes: ocular, papulopustular, and erythematotelangiectatic.^5,6

Continue to: The connection

The connection. Papulopustular and erythematotelangiectatic rosacea may be caused by a proliferation of Demodex mites and increased vascular endothelial growth factor production.² In fact, a proliferation of Demodex is seen in almost all cases of papulopustular rosacea and more than 60% of cases of erythematotelangiectatic rosacea.²

Patient age and distribution of lesions narrowed the differential

Acne vulgaris is an inflammatory disease of the pilosebaceous units caused by increased sebum production, inflammation, and bacterial colonization (Propionibacterium acnes) of hair follicles on the face, neck, chest, and other areas. Both inflammatory and noninflammatory lesions can be present, and in serious cases, scarring can result.⁷ The case patient’s age and accompanying broad erythema were more consistent with rosacea than acne vulgaris.

Seborrheic dermatitis is a common skin condition usually stemming from an inflammatory reaction to a common yeast. Classic symptoms include scaling and erythema of the scalp and central face, as well as pruritus. Topical antifungals such as ketoconazole 2% cream and 2% shampoo are the mainstay of treatment.⁸ The broad distribution and papulopustules in this patient argue against the diagnosis of seborrheic dermatitis.

Systemic lupus erythematosus is a systemic inflammatory disease that often has cutaneous manifestations. Acute lupus manifests as an erythematous “butterfly rash” across the face and cheeks. Chronic discoid lupus involves depigmented plaques, erythematous macules, telangiectasias, and scarring with loss of normal hair follicles. These findings classically are photodistributed.⁹ The classic broad erythema extending from the cheeks over the bridge of the nose was not present in this patient.

Treatment is primarily topical

Mild cases of rosacea often can be managed with topical antibiotic creams. More severe cases may require systemic antibiotics such as tetracycline or doxycycline, although these are used with caution due to the potential for antibiotic resistance.

Ivermectin 1% cream is a US Food and Drug Administration–approved medication that is applied once daily for up to a year to treat the inflammatory pustules associated with Demodex mites. Although it is costly, studies have shown better results with topical ivermectin than with other topical medications (eg, metronidazole 0.75% gel or cream). However, metronidazole 0.75% gel applied twice daily and oral tetracycline 250 mg or doxycycline 100 mg daily or twice daily for at least 2 months often are utilized when the cost of topical ivermectin is prohibitive.¹⁰

Our patient was treated with a combination of doxycycline 100 mg daily for 30 days and ivermectin 1% cream daily. He was also instructed to apply sunscreen daily. He improved rapidly, and the daily topical ivermectin was discontinued after 6 months.

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; [email protected]

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; [email protected]

Ruptured abdominal aortic aneurysms (AAAs) caused about 6000 deaths annually in the United States between 2014 and 2020¹ and are associated with a pooled mortality rate of 81%.² They result from a distinct degenerative process of the layers of the aortic wall.² An AAA is defined as an abdominal aorta whose dilation is > 50% normal (more commonly, a diameter > 3 cm).^3,4 The risk for rupture correlates closely with size; most ruptures occur in aneurysms > 5.5 cm^3,4 (TABLE 1⁵).

Most AAAs are asymptomatic and often go undetected until rupture, resulting in poor outcomes. Because of a low and declining prevalence of AAA and ruptured AAA in developed countries, screening recommendations target high-risk groups rather than the general population.^4,6-8 This review summarizes risk factors, prevalence, and current evidence-based screening and management recommendations for AAA.

Who’s at risk?

Age is the most significant nonmodifiable risk factor, with AAA rupture uncommon in patients younger than 55 years.⁹ One retrospective study found the odds ratio (OR) for diagnosing AAA was 9.41 in adults ages 65 to 69 years (95% CI, 8.76-10.12; P < .0001) and 14.46 (95% CI, 13.45-15.55; P < .0001) in adults ages 70 to 74 years, compared to adults younger than 55 years.¹⁰

Smoking is the most potent modifiable risk factor for AAA. Among patients with AAA, > 90% have a history of smoking.⁴ The association between smoking and AAA is dose dependent, with an OR of 2.61 (95% CI, 2.47-2.74) in patients with a pack-per-year history < 5 years and 12.13 (95% CI, 11.66-12.61) in patients with a pack-per-year history > 35 years, compared to nonsmokers.¹⁰ The risk for AAA increases with smoking duration but decreases with cessation duration.^4,10 Smoking cessation remains an important intervention, as active smokers have higher AAA rupture rates.¹¹

Other risk factors for AAA include concomitant cardiovascular disease (CVD) such as coronary artery disease (CAD), cerebrovascular disease, atherosclerosis, dyslipidemia, and hypertension.¹⁰ Factors associated with reduced risk for AAA include African American race, Hispanic ethnicity, Asian ethnicity, diabetes, smoking cessation, consuming fruits and vegetables > 3 times per week, and exercising more than once per week.^6,10

Prevalence declines but sex-based disparities in outcomes persist

The prevalence of AAA has declined in the United States and Europe in recent decades, correlating with declining rates of smoking.^4,12 Reports published between 2011 and 2019 estimate that AAA prevalence in men older than 60 years has declined over time, with a prevalence of 1.2% to 3.3%.⁶ The prevalence of AAA has also decreased in women,^6,13,14 estimated in 1 study to be as low as 0.74%.¹³ Similarly, deaths from ruptured AAA have declined markedly in the United States—by 70% between 1999 and 2016 according to 1 analysis.⁹

One striking difference in the male-female data is that although AAAs are more common in men, there is a 2- to 4-fold higher risk for rupture in women, who account for nearly half of all AAA-related deaths.^9,10,15-17 The reasons for this heightened risk to women despite lower prevalence are not fully understood but are likely multifactorial and related to a general lack of screening for AAA in women, tendency for AAA to rupture at smaller diameters in women, rupture at an older age in women, and a history of worse surgical outcomes in women than men (though the gap in surgical outcomes appears to be closing).^9,10,18

Continue to: While declines in AAA and AAA-related...

While declines in AAA and AAA-related death are largely attributed to lower smoking rates, other likely contributing factors include the implementation of screening programs, incidental detection during cross-sectional imaging, and improved surgical techniques and management of CV risk factors (eg, hypertension, hyperlipidemia).^9,10

The benefits of screening older men

Randomized controlled trials (RCTs) have demonstrated the benefits of AAA screening programs. A meta-analysis of 4 population­based RCTs of AAA screening in men ≥ 65 years demonstrated statistically significant reductions in AAA rupture (OR = 0.62; 95% CI, 0.55-0.70) and death from AAA (OR = 0.65; 95% CI, 0.57-0.74) over 12 to 15 years, with a number needed to screen (NNS) of 305 (95% CI, 248-411) to prevent 1 AAA-related death.¹⁸ The study also found screening decreases the rate of emergent surgeries for AAA (OR = 0.57; 95% CI, 0.48-0.68) while increasing the number of elective surgeries (OR = 1.44; 95% CI, 1.34-1.55) over 4 to 15 years.¹⁸

Only 1 study has demonstrated an improvement in all-cause mortality with screening programs, with a relatively small benefit (OR = 0.97; 95% CI, 0.94-0.99).¹⁹ Only 1 of the studies included women and, while underpowered, showed no difference in AAA-related death or rupture.²⁰ Guidelines and recommendations of various countries and professional societies focus screening on subgroups at highest risk for AAA.^4,6-8,18

Screening recommendations from USPSTF and others

The US Preventive Services Task Force ­(USPSTF) currently recommends one-time ultrasound screening for AAA in men ages 65 to 75 years who have ever smoked (commonly defined as having smoked > 100 cigarettes) in their lifetime.⁶ This grade “B” recommendation, initially made in 2005 and reaffirmed in the 2014 and 2019 ­USPSTF updates, recommends screening the ­highest-risk segment of the population (ie, older male smokers).⁶

In men ages 65 to 75 years with no smoking history, rather than routine screening, the USPSTF recommends selectively offering screening based on the patient’s medical history, family history, risk factors, and personal values (with a “C” grade).⁶ The USPSTF continues to recommend against screening for AAA in women with no smoking history and no family history of AAA.⁶ According to the USPSTF, the evidence is insufficient to recommend for or against screening women ages 65 to 75 years who have ever smoked or have a family history of AAA (“I” statement).⁶

Continue to: One critique of the USPSTF recommendations

One critique of the USPSTF recommendations is that they fail to detect a significant portion of patients with AAA and AAA rupture. For example, in a retrospective analysis of 55,197 patients undergoing AAA repair, only 33% would have been detected by the USPSTF grade “B” recommendation to screen male smokers ages 65 to 75 years, and an analysis of AAA-related fatalities found 43% would be missed by USPSTF criteria.^9,21

Screening guidelines from the Society for Vascular Surgery (SVS) are broader than those of the USPSTF, in an attempt to capture a larger percentage of the population at risk for AAA-related disease by extrapolating from epidemiologic data. The SVS guidelines include screening for women ages 65 to 75 years with a smoking history, screening men and women ages 65 to 75 years who have a first-degree relative with AAA, and consideration of screening patients older than 75 years if they are in good health and have a first-degree relative with AAA or a smoking history and have not been previously screened.⁴ However, these expanded recommendations are not supported by patient-oriented evidence.⁶

Attempts to broaden screening guidelines must be tempered by potential risks for harm, primarily overdiagnosis (ie, diagnosing AAAs that would not otherwise rise to clinical significance) and overtreatment (ie, resulting in unnecessary imaging, appointments, anxiety, or surgery). Negative psychological effects on quality of life after a diagnosis of AAA have not been shown to cause significant harm.^6,18

A recent UK analysis found that screening programs for AAA in women modeled after those in men are not cost effective, with an NNS to prevent 1 death of 3900 in women vs 700 in men.^15,18 Another recent trial of ultrasound screening in 5200 high-risk women ages 65 to 74 years found an AAA incidence of 0.29% (95% CI, 0.18%-0.48%) in which only 3 large aneurysms were identified.²²

Smoking is the most potent modifiable risk factor for abdominal aortic aneurysm.

In the United States, rates of screening for AAA remain low.²³ One study has shown electronic medical record–based reminders increased screening rates from 48% to 80%.²⁴ Point-of-care bedside ultrasound performed by clinicians also could improve screening rates. Multiple studies have demonstrated that screening and diagnosis of AAA can be performed safely and effectively at the bedside by nonradiologists such as family physicians and emergency physicians.^25-28 In 1 study, such exams added < 4 minutes to the patient encounter.²⁶ Follow-up surveillance schedules for those identified as having a AAA are summarized in TABLE 2.⁴

Continue to: Management options

Management options: Immediate repair or surveillance?

After diagnosing AAA, important decisions must be made regarding management, including indications for surgical repair, appropriate follow-up surveillance, and medications for secondary prevention and cardiovascular risk reduction.

EVAR vs open repair

The 2 main surgical strategies for aneurysm repair are open repair and endovascular repair (EVAR). In the United States, EVAR is becoming the more common approach and was used to repair asymptomatic aneurysms in > 80% of patients and ruptured aneurysms in 50% of patients.⁶ There have been multiple RCTs assessing EVAR and open repair for large and small aneurysms.^29-34 Findings across these studies consistently show EVAR is associated with lower immediate (ie, ­30-day) morbidity and mortality but no ­longer-term survival benefit compared to open repair.

EVAR procedures require ongoing long-term surveillance for endovascular leakage and other complications, resulting in an increased need for re-intervention.^31,33,35 For these reasons, the National Institute for Health and Care Excellence (NICE) guidelines suggest open repair as the preferred modality.⁷ However, SVS and the American College of Cardiology Foundation/American Heart Association guidance support either EVAR or open repair, noting that open repair may be preferable in patients unable to engage in long-term follow-up surveillance.³⁶

Indications for repair. In general, repair is indicated when an aneurysm reaches or exceeds 5.5 cm.^4,7 Both SVS and NICE also recommend clinicians consider surgical repair of smaller, rapidly expanding aneurysms (> 1 cm over a 1-year period).^4,7 Based on evidence suggesting a higher risk for rupture in women with smaller aneurysms,^14,37 SVS recommends clinicians consider surgical repair in women with an AAA ≥ 5.0 cm. Several RCTs evaluating the benefits of immediate repair for smaller-sized aneurysms (4.0-5.5 cm) favored surveillance.^38,39 Accepted indications for surgical repair are summarized in TABLE 3.^4,7,34Surgical repair recommendations also are based on aneurysm morphology, which can be fusiform or saccular (FIGURE). More than 90% of AAAs are fusiform.⁴⁰ Although saccular AAAs are less common, some studies suggest they are more prone to rupture than fusiform AAAs, and SVS guidelines suggest surgical repair of saccular aneurysms regardless of size.^4,41,42

Perioperative and long-term risks. Both EVAR and open repair of AAA carry a high perioperative and long-term risk for death, as patients often have multiple comorbidities. A 2019 trial comparing EVAR to open repair with 14 years of follow-up reported death in 68% of patients in the EVAR group and 70% in the open repair group. ³¹ Among these deaths, 2.7% in the EVAR group and 3.7% in the open repair group were aneurysm related.³¹ The study also found a second surgical intervention was required in 19.8% of patients in the open repair group and 26.7% in the EVAR group.³¹

Continue to: When assessing perioperative risk...

Although abdominal aortic aneurysms are more common in men, there is a 2- to 4-fold higher risk for rupture in women.

When assessing perioperative risk, SVS guidelines recommend clinicians employ a shared decision-making approach with patients that incorporates Vascular Quality Initiative (VQI) mortality risk score.⁴ (VQI risk calculators are available at https://qxmd.com/vascular-study-group-new-england-decision-support-tools.⁴³)

Medication management

Based on the close association of aortic aneurysm with atherosclerotic CVD (ASCVD), professional societies such as the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have suggested aortic aneurysm is equivalent to ASCVD and should be managed medically in a similar manner to peripheral arterial disease.⁴⁴ Indeed, many patients with AAA may have concomitant CAD or other arterial vascular diseases (eg, carotid, lower extremity).

Statins. In its guidelines, the ESC/EAS consider patients with AAA at “very high risk” for adverse CV events and suggest pharmacotherapy with high-intensity statins, adding ezetimibe or proprotein convertase ­subtilisin/kexin type 9 (PCSK9) inhibitors if needed, to reduce low-density lipoprotein cholesterol ≥ 50% from baseline, with a goal of < 55 mg/dL.⁴⁴ Statin therapy additionally lowers all-cause postoperative mortality in patients undergoing AAA repair but does not affect the rate of aneurysm expansion.⁴⁵

Aspirin and other anticoagulants. Although aspirin therapy may be indicated for the secondary prevention of other cardiovascular events that may coexist with AAA, it does not appear to affect the rate of growth or prevent rupture of aneurysms.^46,47 In addition to aspirin, anticoagulants such as clopidogrel, enoxaparin, and warfarin are not recommended when the presence of AAA is the only indication.⁴

The USPSTF continues to recommend against screening in women with no smoking history and no family history of abdominal aortic aneurysm.

Other medications. Angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and antibiotics (eg, doxycycline) have been studied as a treatment for AAA. However, none has shown benefit in reducing aneurysm growth or rupture and they are not recommended for that sole purpose.^4,48

Metformin. There is a negative association between diabetes and AAA expansion and rupture. Several cohort studies have indicated that this may be an independent effect driven primarily by exposure to metformin. While it is not unreasonable to consider this another important indication for metformin use in patients with diabetes, RCT evidence has yet to establish a role for metformin in patients without diabetes who have AAA.^48,49

ACKNOWLEDGEMENT
The authors thank Gwen Wilson, MLS, AHIP, for her assistance with the literature searches performed in the preparation of this manuscript.

CORRESPONDENCE
Nicholas LeFevre, MD, Family and Community Medicine, University of Missouri–Columbia School of Medicine, One Hospital Drive, M224 Medical Science Building, Columbia, MO 65212; [email protected]

Gastroesophageal reflux disease (GERD) encompasses various syndromes and complications associated with abnormal movement of gastric refluxate from the stomach into the esophagus, and even into the oral pharynx, lungs, and throat.

Read More

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Gastroesophageal reflux disease (GERD) encompasses various syndromes and complications associated with abnormal movement of gastric refluxate from the stomach into the esophagus, and even into the oral pharynx, lungs, and throat.

Read More

‌

‌

‌

Gastroesophageal reflux disease (GERD) encompasses various syndromes and complications associated with abnormal movement of gastric refluxate from the stomach into the esophagus, and even into the oral pharynx, lungs, and throat.

Read More

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CASE Sexually active woman asks about the HPV vaccine

A 26-year-old woman delivered her first child 4 weeks ago. She has had 3 lifetime sexual partners and is now in a mutually faithful monogamous relationship with her partner. She has no known history of sexually transmissible infections. She received only one Pap test 3 years ago, and the cytology showed no abnormal cells. This cervical specimen was not tested for human papillomavirus (HPV) DNA. At the time of her postpartum appointment, she inquires whether she is a candidate for the HPV vaccine.

What should be your response?
 

Genital HPV infection is the most common sexually transmissible infection in the United States. This virus is the cause of multiple genital malignancies, including cancers of the vagina, vulva, penis, anus, and cervix. The organism is also now the major cause of oropharyngeal cancer.

Of the more than 200 different HPV types that have been identified, 12 have been defined as oncogenic (high risk), and 8 to 12 types have been defined as possibly or probably oncogenic. The HPV strain with the highest risk of progression to cancer is HPV 16. The strains HPV 16 and 18 are responsible for approximately 70% of cases of cervical cancer. Each year in the United States, approximately 11,500 new cases of invasive cervical cancer occur. Unfortunately, this malignancy is responsible for about 4,000 deaths annually. Worldwide, HPV causes approximately 690,000 cancers each year.¹

To a large extent, most cases of HPV infection would be preventable if patients were to take advantage of the remarkably effective HPV vaccine that is now available. However, acceptance of the vaccine has been disappointing. In 2020, only about half of adolescents, age 13 to 15, had received the appropriate number of vaccine doses.¹

As ObGyn physicians, we can take several measures, in concert with our pediatrician colleagues, to improve HPV vaccination rates. In this article, I review the development of the HPV vaccine and describe the components, indications, dosing schedules, contraindications, adverse effects, and cost of the vaccine.

HPV vaccine development and expansion

The first HPV vaccine introduced in the United States was the recombinant quadrivalent vaccine (Gardasil; Merck); it was approved by the US Food and Drug Administration (FDA) in 2006. This vaccine is composed of viral-like particles unique to HPV 16 and 18 (the 2 most common causes of cervical, penile, anal, and oropharyngeal cancer) and HPV 6 and 11 (the 2 most common causes of genital warts). The formulation is prepared in baker’s yeast, and it elicits a robust production of neutralizing antibodies.²

In 2009, the FDA approved the bivalent vaccine (Cervarix; GlaxoSmithKline Biologicals). This vaccine contains viral-like particles unique to HPV 16 and 18, and it also induces a robust immune response. The vaccine is prepared in insect viral vectors.²

Both the quadrivalent and bivalent vaccines are no longer available in the United States. The only HPV vaccine currently marketed is the recombinant 9-valent vaccine (Gardasil 9; Merck), which was approved by the FDA in 2014. This newer vaccine targets the original 4 viral HPV strains in the quadrivalent vaccine (16, 18, 6, 11) plus 5 additional oncogenic strains: 31, 33, 45, 52, 58.^2-4 The HPV strains targeted by this vaccine are responsible for approximately 90% of all cancers caused by HPV.

The 9-valent HPV vaccine, like the other 2, is highly effective in preventing cancers of the cervix, vagina, vulva, anus, penis; oropharyngeal cancers; and precancerous lesions such as genital warts.^2-5 It will not, however, prevent the progression of preexisting infection or clear an infection that is already present at the time of vaccination.¹

Although the original protocol for administration of the vaccine provided for 3 doses, recent studies indicate that 2 doses may be as effective as 3 in eliciting a favorable antibody response.⁶ There also is evidence that even a single dose of the vaccine can elicit a protective immune response.⁷ This encouraging finding is particularly important to public health officials responsible for developing HPV vaccination programs in low- and middle-resource countries.

Continue to: Target groups for the HPV vaccine...

Target groups for the HPV vaccine

The primary target group for the HPV vaccine is girls and boys who are aged 11 to 12 years. The key strategy is to immunize these individuals before they become sexually active. The vaccine also should be offered to children who are aged 9 to 10 years of age if they are judged to be at unusual risk, such as because of concern about sexual molestation. Children in these 2 age groups should receive 2 doses of the vaccine, with the second dose administered 6 to 12 months after the first dose.

The second target group for vaccination is individuals who are aged 13 to 26 years who have never been vaccinated. They should be offered catch-up vaccination. If older than age 15, they should receive 3 doses of the vaccine, with the second dose administered 1 to 2 months after the first dose and the third dose administered 6 months after the first dose.¹

A third target group is individuals who are aged 27 to 45 years and who, in their own opinion or in the opinion of their physician, are at new or increased risk for HPV infection. These individuals should receive the 3-dose vaccine series as outlined above.¹

Patients in any age range who are immunocompromised, for example, due to HIV infection, should receive the 3-dose series.¹

The approximate retail cost of a single 0.5-mL intramuscular dose of the 9-valent vaccine is $240 (www.goodrx.com).

Vaccine adverse effects

The most common reactions to the HPV vaccine are inflammation at the site of injection, fatigue, headache, fever, gastrointestinal upset, vertigo, cough, and oropharyngeal discomfort. The most serious reaction—which fortunately is very rare—is anaphylaxis.¹

Contraindications to the vaccine

The HPV vaccine should not be used in any patient who is hypersensitive to any component of the vaccine, including yeast. It should not be given to a patient who is moderately or severely ill at the time of the scheduled administration. Because of an abundance of caution, the manufacturer also recommends that the vaccine not be given to pregnant women even though the agent does not contain live virus.¹

Of note, a study by Scheller and colleagues was very reassuring about the lack of adverse effects of HPV vaccine administration in pregnancy.⁸ The authors evaluated a large cohort of pregnant women in Demark and found that exposure to the vaccine was not associated with an increase in the frequency of major birth defects, spontaneous abortion, preterm delivery, low birthweight, fetal growth restriction, or stillbirth.⁸

Barriers to vaccination

One important barrier to HPV vaccination is patient apprehension that the vaccine may cause genital tract or oropharyngeal cancer. The patient should be reassured that the vaccine does not contain infectious viral particles and does not transmit infection. Rather, it builds robust immunity to infection.

Another important barrier is the misconception that the vaccine will promote sexual promiscuity in preteenagers and teenagers. Absolutely no evidence supports this belief. Multiple studies have demonstrated that teenagers do not engage in more high-risk sexual behavior following vaccination.

A specific barrier related to vaccination of young boys is the philosophical viewpoint that, “Why should my young male child be vaccinated to protect against a disease (specifically cervical cancer) that occurs only in girls and women?” The appropriate answer to this question is that the vaccine also protects against penile cancer, anal cancer, oropharyngeal cancer, and genital warts. While penile and anal cancers are rare, the other 2 conditions are not. In fact, oropharyngeal cancer is significantly more common in males than females.

A final important barrier to HPV vaccination is cost. The new evidence that demonstrated the effectiveness of a 2-dose vaccine series, and even single-dose vaccination, is of great importance in minimizing cost of the HPV vaccine series, in the absence of full reimbursement by public and private insurance agencies.

Continue to: Creating an effective vaccination program...

Creating an effective vaccination program

The following commonsense guidelines, which we have implemented at our medical center, should be helpful in organizing an effective HPV vaccination program for your office or department^4,9,10:

• One clinician in the department or practice should be designated the “vaccination champion.” This individual should provide colleagues with periodic updates, emphasizing the importance of the HPV vaccine and other vaccines, such as Tdap (tetanus, diphtheria, pertussis), influenza, COVID, pneumococcal, hepatitis B, herpes zoster (shingles), and RSV (respiratory syncytial virus).
• One staff member in the practice or department should be designated as the go-to person for all logistical matters related to vaccines. This individual should be responsible for estimating usage, ordering vaccines, and storing them properly. He or she also should be knowledgeable about the cost of the vaccines and insurance reimbursement for the vaccines.
• Signs and educational materials should be posted in strategic locations in the office, advising patients of the importance of timely vaccination for themselves and their adolescent children.
• At every encounter, patients should be encouraged to receive the HPV vaccine series if they are in the appropriate age range and social situation for vaccination. They should not be required to have HPV testing before vaccine administration.
• Key leaders in the department or practice should lobby effectively with their pediatrician colleagues and with public and private insurance companies to encourage timely administration and proper coverage of this important immunization.

Other measures to reduce the risk of HPV-mediated malignancies

Practitioners should advise their patients to:

• Be circumspect in selection of sexual partners.
• Use male or female condoms when engaging in vaginal, anal, and/or oral sex with multiple partners, particularly those who may have genital or oral condylomas.
• Have regular Pap tests, every 3 to 5 years, depending upon age. More frequent testing may be indicated if there is a history of previous abnormal testing.
• Seek prompt medical or surgical treatment for genital or oral condylomas.

CASE Resolved with HPV vaccination

This patient is an excellent candidate for catch-up vaccination. She should receive the first dose of the 9-valent HPV vaccine at the time of her postpartum appointment. The second dose should be administered 1 to 2 months later. The third dose should be administered 6 months after the first dose. She also should have a Pap test, either cytology alone or cytology plus HPV screening. If the latter test is chosen and is reassuring, she will not need retesting for 5 years. If the former test is chosen, she should have a repeat test in 3 years. ●

CASE Sexually active woman asks about the HPV vaccine

A 26-year-old woman delivered her first child 4 weeks ago. She has had 3 lifetime sexual partners and is now in a mutually faithful monogamous relationship with her partner. She has no known history of sexually transmissible infections. She received only one Pap test 3 years ago, and the cytology showed no abnormal cells. This cervical specimen was not tested for human papillomavirus (HPV) DNA. At the time of her postpartum appointment, she inquires whether she is a candidate for the HPV vaccine.

What should be your response?
 

Genital HPV infection is the most common sexually transmissible infection in the United States. This virus is the cause of multiple genital malignancies, including cancers of the vagina, vulva, penis, anus, and cervix. The organism is also now the major cause of oropharyngeal cancer.

Of the more than 200 different HPV types that have been identified, 12 have been defined as oncogenic (high risk), and 8 to 12 types have been defined as possibly or probably oncogenic. The HPV strain with the highest risk of progression to cancer is HPV 16. The strains HPV 16 and 18 are responsible for approximately 70% of cases of cervical cancer. Each year in the United States, approximately 11,500 new cases of invasive cervical cancer occur. Unfortunately, this malignancy is responsible for about 4,000 deaths annually. Worldwide, HPV causes approximately 690,000 cancers each year.¹

To a large extent, most cases of HPV infection would be preventable if patients were to take advantage of the remarkably effective HPV vaccine that is now available. However, acceptance of the vaccine has been disappointing. In 2020, only about half of adolescents, age 13 to 15, had received the appropriate number of vaccine doses.¹

As ObGyn physicians, we can take several measures, in concert with our pediatrician colleagues, to improve HPV vaccination rates. In this article, I review the development of the HPV vaccine and describe the components, indications, dosing schedules, contraindications, adverse effects, and cost of the vaccine.

HPV vaccine development and expansion

The first HPV vaccine introduced in the United States was the recombinant quadrivalent vaccine (Gardasil; Merck); it was approved by the US Food and Drug Administration (FDA) in 2006. This vaccine is composed of viral-like particles unique to HPV 16 and 18 (the 2 most common causes of cervical, penile, anal, and oropharyngeal cancer) and HPV 6 and 11 (the 2 most common causes of genital warts). The formulation is prepared in baker’s yeast, and it elicits a robust production of neutralizing antibodies.²

In 2009, the FDA approved the bivalent vaccine (Cervarix; GlaxoSmithKline Biologicals). This vaccine contains viral-like particles unique to HPV 16 and 18, and it also induces a robust immune response. The vaccine is prepared in insect viral vectors.²

Both the quadrivalent and bivalent vaccines are no longer available in the United States. The only HPV vaccine currently marketed is the recombinant 9-valent vaccine (Gardasil 9; Merck), which was approved by the FDA in 2014. This newer vaccine targets the original 4 viral HPV strains in the quadrivalent vaccine (16, 18, 6, 11) plus 5 additional oncogenic strains: 31, 33, 45, 52, 58.^2-4 The HPV strains targeted by this vaccine are responsible for approximately 90% of all cancers caused by HPV.

The 9-valent HPV vaccine, like the other 2, is highly effective in preventing cancers of the cervix, vagina, vulva, anus, penis; oropharyngeal cancers; and precancerous lesions such as genital warts.^2-5 It will not, however, prevent the progression of preexisting infection or clear an infection that is already present at the time of vaccination.¹

Although the original protocol for administration of the vaccine provided for 3 doses, recent studies indicate that 2 doses may be as effective as 3 in eliciting a favorable antibody response.⁶ There also is evidence that even a single dose of the vaccine can elicit a protective immune response.⁷ This encouraging finding is particularly important to public health officials responsible for developing HPV vaccination programs in low- and middle-resource countries.

Continue to: Target groups for the HPV vaccine...

Target groups for the HPV vaccine

The primary target group for the HPV vaccine is girls and boys who are aged 11 to 12 years. The key strategy is to immunize these individuals before they become sexually active. The vaccine also should be offered to children who are aged 9 to 10 years of age if they are judged to be at unusual risk, such as because of concern about sexual molestation. Children in these 2 age groups should receive 2 doses of the vaccine, with the second dose administered 6 to 12 months after the first dose.

The second target group for vaccination is individuals who are aged 13 to 26 years who have never been vaccinated. They should be offered catch-up vaccination. If older than age 15, they should receive 3 doses of the vaccine, with the second dose administered 1 to 2 months after the first dose and the third dose administered 6 months after the first dose.¹

A third target group is individuals who are aged 27 to 45 years and who, in their own opinion or in the opinion of their physician, are at new or increased risk for HPV infection. These individuals should receive the 3-dose vaccine series as outlined above.¹

Patients in any age range who are immunocompromised, for example, due to HIV infection, should receive the 3-dose series.¹

The approximate retail cost of a single 0.5-mL intramuscular dose of the 9-valent vaccine is $240 (www.goodrx.com).

Vaccine adverse effects

The most common reactions to the HPV vaccine are inflammation at the site of injection, fatigue, headache, fever, gastrointestinal upset, vertigo, cough, and oropharyngeal discomfort. The most serious reaction—which fortunately is very rare—is anaphylaxis.¹

Contraindications to the vaccine

The HPV vaccine should not be used in any patient who is hypersensitive to any component of the vaccine, including yeast. It should not be given to a patient who is moderately or severely ill at the time of the scheduled administration. Because of an abundance of caution, the manufacturer also recommends that the vaccine not be given to pregnant women even though the agent does not contain live virus.¹

Of note, a study by Scheller and colleagues was very reassuring about the lack of adverse effects of HPV vaccine administration in pregnancy.⁸ The authors evaluated a large cohort of pregnant women in Demark and found that exposure to the vaccine was not associated with an increase in the frequency of major birth defects, spontaneous abortion, preterm delivery, low birthweight, fetal growth restriction, or stillbirth.⁸

Barriers to vaccination

One important barrier to HPV vaccination is patient apprehension that the vaccine may cause genital tract or oropharyngeal cancer. The patient should be reassured that the vaccine does not contain infectious viral particles and does not transmit infection. Rather, it builds robust immunity to infection.

Another important barrier is the misconception that the vaccine will promote sexual promiscuity in preteenagers and teenagers. Absolutely no evidence supports this belief. Multiple studies have demonstrated that teenagers do not engage in more high-risk sexual behavior following vaccination.

A specific barrier related to vaccination of young boys is the philosophical viewpoint that, “Why should my young male child be vaccinated to protect against a disease (specifically cervical cancer) that occurs only in girls and women?” The appropriate answer to this question is that the vaccine also protects against penile cancer, anal cancer, oropharyngeal cancer, and genital warts. While penile and anal cancers are rare, the other 2 conditions are not. In fact, oropharyngeal cancer is significantly more common in males than females.

A final important barrier to HPV vaccination is cost. The new evidence that demonstrated the effectiveness of a 2-dose vaccine series, and even single-dose vaccination, is of great importance in minimizing cost of the HPV vaccine series, in the absence of full reimbursement by public and private insurance agencies.

Continue to: Creating an effective vaccination program...

Creating an effective vaccination program

The following commonsense guidelines, which we have implemented at our medical center, should be helpful in organizing an effective HPV vaccination program for your office or department^4,9,10:

• One clinician in the department or practice should be designated the “vaccination champion.” This individual should provide colleagues with periodic updates, emphasizing the importance of the HPV vaccine and other vaccines, such as Tdap (tetanus, diphtheria, pertussis), influenza, COVID, pneumococcal, hepatitis B, herpes zoster (shingles), and RSV (respiratory syncytial virus).
• One staff member in the practice or department should be designated as the go-to person for all logistical matters related to vaccines. This individual should be responsible for estimating usage, ordering vaccines, and storing them properly. He or she also should be knowledgeable about the cost of the vaccines and insurance reimbursement for the vaccines.
• Signs and educational materials should be posted in strategic locations in the office, advising patients of the importance of timely vaccination for themselves and their adolescent children.
• At every encounter, patients should be encouraged to receive the HPV vaccine series if they are in the appropriate age range and social situation for vaccination. They should not be required to have HPV testing before vaccine administration.
• Key leaders in the department or practice should lobby effectively with their pediatrician colleagues and with public and private insurance companies to encourage timely administration and proper coverage of this important immunization.

Other measures to reduce the risk of HPV-mediated malignancies

Practitioners should advise their patients to:

• Be circumspect in selection of sexual partners.
• Use male or female condoms when engaging in vaginal, anal, and/or oral sex with multiple partners, particularly those who may have genital or oral condylomas.
• Have regular Pap tests, every 3 to 5 years, depending upon age. More frequent testing may be indicated if there is a history of previous abnormal testing.
• Seek prompt medical or surgical treatment for genital or oral condylomas.

CASE Resolved with HPV vaccination

This patient is an excellent candidate for catch-up vaccination. She should receive the first dose of the 9-valent HPV vaccine at the time of her postpartum appointment. The second dose should be administered 1 to 2 months later. The third dose should be administered 6 months after the first dose. She also should have a Pap test, either cytology alone or cytology plus HPV screening. If the latter test is chosen and is reassuring, she will not need retesting for 5 years. If the former test is chosen, she should have a repeat test in 3 years. ●

CASE Sexually active woman asks about the HPV vaccine

A 26-year-old woman delivered her first child 4 weeks ago. She has had 3 lifetime sexual partners and is now in a mutually faithful monogamous relationship with her partner. She has no known history of sexually transmissible infections. She received only one Pap test 3 years ago, and the cytology showed no abnormal cells. This cervical specimen was not tested for human papillomavirus (HPV) DNA. At the time of her postpartum appointment, she inquires whether she is a candidate for the HPV vaccine.

What should be your response?
 

Genital HPV infection is the most common sexually transmissible infection in the United States. This virus is the cause of multiple genital malignancies, including cancers of the vagina, vulva, penis, anus, and cervix. The organism is also now the major cause of oropharyngeal cancer.

Of the more than 200 different HPV types that have been identified, 12 have been defined as oncogenic (high risk), and 8 to 12 types have been defined as possibly or probably oncogenic. The HPV strain with the highest risk of progression to cancer is HPV 16. The strains HPV 16 and 18 are responsible for approximately 70% of cases of cervical cancer. Each year in the United States, approximately 11,500 new cases of invasive cervical cancer occur. Unfortunately, this malignancy is responsible for about 4,000 deaths annually. Worldwide, HPV causes approximately 690,000 cancers each year.¹

To a large extent, most cases of HPV infection would be preventable if patients were to take advantage of the remarkably effective HPV vaccine that is now available. However, acceptance of the vaccine has been disappointing. In 2020, only about half of adolescents, age 13 to 15, had received the appropriate number of vaccine doses.¹

As ObGyn physicians, we can take several measures, in concert with our pediatrician colleagues, to improve HPV vaccination rates. In this article, I review the development of the HPV vaccine and describe the components, indications, dosing schedules, contraindications, adverse effects, and cost of the vaccine.

HPV vaccine development and expansion

The first HPV vaccine introduced in the United States was the recombinant quadrivalent vaccine (Gardasil; Merck); it was approved by the US Food and Drug Administration (FDA) in 2006. This vaccine is composed of viral-like particles unique to HPV 16 and 18 (the 2 most common causes of cervical, penile, anal, and oropharyngeal cancer) and HPV 6 and 11 (the 2 most common causes of genital warts). The formulation is prepared in baker’s yeast, and it elicits a robust production of neutralizing antibodies.²

In 2009, the FDA approved the bivalent vaccine (Cervarix; GlaxoSmithKline Biologicals). This vaccine contains viral-like particles unique to HPV 16 and 18, and it also induces a robust immune response. The vaccine is prepared in insect viral vectors.²

Both the quadrivalent and bivalent vaccines are no longer available in the United States. The only HPV vaccine currently marketed is the recombinant 9-valent vaccine (Gardasil 9; Merck), which was approved by the FDA in 2014. This newer vaccine targets the original 4 viral HPV strains in the quadrivalent vaccine (16, 18, 6, 11) plus 5 additional oncogenic strains: 31, 33, 45, 52, 58.^2-4 The HPV strains targeted by this vaccine are responsible for approximately 90% of all cancers caused by HPV.

The 9-valent HPV vaccine, like the other 2, is highly effective in preventing cancers of the cervix, vagina, vulva, anus, penis; oropharyngeal cancers; and precancerous lesions such as genital warts.^2-5 It will not, however, prevent the progression of preexisting infection or clear an infection that is already present at the time of vaccination.¹

Although the original protocol for administration of the vaccine provided for 3 doses, recent studies indicate that 2 doses may be as effective as 3 in eliciting a favorable antibody response.⁶ There also is evidence that even a single dose of the vaccine can elicit a protective immune response.⁷ This encouraging finding is particularly important to public health officials responsible for developing HPV vaccination programs in low- and middle-resource countries.

Continue to: Target groups for the HPV vaccine...

Target groups for the HPV vaccine

The primary target group for the HPV vaccine is girls and boys who are aged 11 to 12 years. The key strategy is to immunize these individuals before they become sexually active. The vaccine also should be offered to children who are aged 9 to 10 years of age if they are judged to be at unusual risk, such as because of concern about sexual molestation. Children in these 2 age groups should receive 2 doses of the vaccine, with the second dose administered 6 to 12 months after the first dose.

The second target group for vaccination is individuals who are aged 13 to 26 years who have never been vaccinated. They should be offered catch-up vaccination. If older than age 15, they should receive 3 doses of the vaccine, with the second dose administered 1 to 2 months after the first dose and the third dose administered 6 months after the first dose.¹

A third target group is individuals who are aged 27 to 45 years and who, in their own opinion or in the opinion of their physician, are at new or increased risk for HPV infection. These individuals should receive the 3-dose vaccine series as outlined above.¹

Patients in any age range who are immunocompromised, for example, due to HIV infection, should receive the 3-dose series.¹

The approximate retail cost of a single 0.5-mL intramuscular dose of the 9-valent vaccine is $240 (www.goodrx.com).

Vaccine adverse effects

The most common reactions to the HPV vaccine are inflammation at the site of injection, fatigue, headache, fever, gastrointestinal upset, vertigo, cough, and oropharyngeal discomfort. The most serious reaction—which fortunately is very rare—is anaphylaxis.¹

Contraindications to the vaccine

The HPV vaccine should not be used in any patient who is hypersensitive to any component of the vaccine, including yeast. It should not be given to a patient who is moderately or severely ill at the time of the scheduled administration. Because of an abundance of caution, the manufacturer also recommends that the vaccine not be given to pregnant women even though the agent does not contain live virus.¹

Of note, a study by Scheller and colleagues was very reassuring about the lack of adverse effects of HPV vaccine administration in pregnancy.⁸ The authors evaluated a large cohort of pregnant women in Demark and found that exposure to the vaccine was not associated with an increase in the frequency of major birth defects, spontaneous abortion, preterm delivery, low birthweight, fetal growth restriction, or stillbirth.⁸

Barriers to vaccination

One important barrier to HPV vaccination is patient apprehension that the vaccine may cause genital tract or oropharyngeal cancer. The patient should be reassured that the vaccine does not contain infectious viral particles and does not transmit infection. Rather, it builds robust immunity to infection.

Another important barrier is the misconception that the vaccine will promote sexual promiscuity in preteenagers and teenagers. Absolutely no evidence supports this belief. Multiple studies have demonstrated that teenagers do not engage in more high-risk sexual behavior following vaccination.

A specific barrier related to vaccination of young boys is the philosophical viewpoint that, “Why should my young male child be vaccinated to protect against a disease (specifically cervical cancer) that occurs only in girls and women?” The appropriate answer to this question is that the vaccine also protects against penile cancer, anal cancer, oropharyngeal cancer, and genital warts. While penile and anal cancers are rare, the other 2 conditions are not. In fact, oropharyngeal cancer is significantly more common in males than females.

A final important barrier to HPV vaccination is cost. The new evidence that demonstrated the effectiveness of a 2-dose vaccine series, and even single-dose vaccination, is of great importance in minimizing cost of the HPV vaccine series, in the absence of full reimbursement by public and private insurance agencies.

Continue to: Creating an effective vaccination program...

Creating an effective vaccination program

The following commonsense guidelines, which we have implemented at our medical center, should be helpful in organizing an effective HPV vaccination program for your office or department^4,9,10:

• One clinician in the department or practice should be designated the “vaccination champion.” This individual should provide colleagues with periodic updates, emphasizing the importance of the HPV vaccine and other vaccines, such as Tdap (tetanus, diphtheria, pertussis), influenza, COVID, pneumococcal, hepatitis B, herpes zoster (shingles), and RSV (respiratory syncytial virus).
• One staff member in the practice or department should be designated as the go-to person for all logistical matters related to vaccines. This individual should be responsible for estimating usage, ordering vaccines, and storing them properly. He or she also should be knowledgeable about the cost of the vaccines and insurance reimbursement for the vaccines.
• Signs and educational materials should be posted in strategic locations in the office, advising patients of the importance of timely vaccination for themselves and their adolescent children.
• At every encounter, patients should be encouraged to receive the HPV vaccine series if they are in the appropriate age range and social situation for vaccination. They should not be required to have HPV testing before vaccine administration.
• Key leaders in the department or practice should lobby effectively with their pediatrician colleagues and with public and private insurance companies to encourage timely administration and proper coverage of this important immunization.

Other measures to reduce the risk of HPV-mediated malignancies

Practitioners should advise their patients to:

• Be circumspect in selection of sexual partners.
• Use male or female condoms when engaging in vaginal, anal, and/or oral sex with multiple partners, particularly those who may have genital or oral condylomas.
• Have regular Pap tests, every 3 to 5 years, depending upon age. More frequent testing may be indicated if there is a history of previous abnormal testing.
• Seek prompt medical or surgical treatment for genital or oral condylomas.

CASE Resolved with HPV vaccination

This patient is an excellent candidate for catch-up vaccination. She should receive the first dose of the 9-valent HPV vaccine at the time of her postpartum appointment. The second dose should be administered 1 to 2 months later. The third dose should be administered 6 months after the first dose. She also should have a Pap test, either cytology alone or cytology plus HPV screening. If the latter test is chosen and is reassuring, she will not need retesting for 5 years. If the former test is chosen, she should have a repeat test in 3 years. ●

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

THE COMPARISON

A An 11-year-old Hispanic boy with allergic contact dermatitis (ACD) on the abdomen. The geometric nature of the eruption and proximity to the belt buckle were highly suggestive of ACD to nickel; patch testing was not needed.

B A Black woman with ACD on the neck. A punch biopsy demonstrated spongiotic dermatitis that was typical of ACD. The diagnosis was supported by the patient’s history of dermatitis that developed after new products were applied to the hair. The patient declined patch testing.

C A Hispanic man with ACD on hair-bearing areas of the face where hair dye was used. The patient’s history of dermatitis following the application of hair dye was highly suggestive of ACD; patch testing confirmed the allergen was paraphenylenediamine (PPD).

Allergic contact dermatitis (ACD) is an inflammatory condition of the skin caused by an immunologic response to 1 or more identifiable allergens. A delayed-type immune response (type IV hypersensitivity reaction) occurs after the skin is re-exposed to an offending allergen.¹ Severe pruritus is the main symptom of ACD in the early stages, accompanied by erythema, vesicles, and scaling in a distinct pattern corresponding to the allergen’s contact with the skin.² Delayed widespread dermatitis after exposure to an allergen—a phenomenon known as autoeczematization (id reaction)—also may occur.³

The gold-standard diagnostic tool for ACD is patch testing, in which the patient is re-exposed to the suspected contact allergen(s) and observed for the development of dermatitis.⁴ However, ACD can be diagnosed with a detailed patient history including occupation, hobbies, personal care practices, and possible triggers with subsequent rashes. Thorough clinical examination of the skin is paramount. Indicators of possible ACD include dermatitis that persists despite use of appropriate treatment, an unexplained flare of previously quiescent dermatitis, and a diagnosis of dermatitis without a clear cause.¹

Hairdressers, health care workers, and metal workers are at higher risk for ACD.⁵ Occupational ACD has notable socioeconomic implications, as it can result in frequent sick days, inability to perform tasks at work, and in some cases job loss.⁶

Patients with atopic dermatitis have impaired barrier function of the skin, permitting the entrance of allergens and subsequent sensitization.⁷ ACD is a challenge to manage, as complete avoidance of the allergen may not be possible.⁸

Continue to: The underrepresentation of patients...

The underrepresentation of patients with skin of color (SOC) in educational materials as well as socioeconomic health disparities may contribute to the lower rates of diagnosis, patch testing, and treatment of ACD in this patient population.

Epidemiology

An ACD prevalence of 15.2% was reported in a study of 793 Danish patients who underwent skin prick and patch testing.⁹ Alinaghi et al¹⁰ conducted a meta-analysis of 20,107 patients across 28 studies who were patch tested to determine the prevalence of ACD in the general population. The researchers concluded that 20.1% (95% CI, 16.8%-23.7%) of the general population experienced ACD. They analyzed 22 studies to determine the prevalence of ACD based on specific geographic area, including 18,709 individuals from Europe with a prevalence of 19.5% (95% CI, 15.8%-23.4%), 1639 individuals from North America with a prevalence of 20.6% (95% CI, 9.2%-35.2%), and 2 studies from China (no other studies from Asia found) with a prevalence of 20.6% (95% CI, 17.4%-23.9%). Researchers did not find data from studies conducted in Africa or South America.¹⁰

The current available epidemiologic data on ACD are not representative of SOC populations. DeLeo et al¹¹ looked at patch test reaction patterns in association with race and ethnicity in a large sample size (N = 19,457); 92.9% of these patients were White and only 7.1% were Black. Large-scale, inclusive studies are needed, which can only be achieved with increased suspicion for ACD and increased access to patch testing.

ACD is more common in women, with nickel being the most frequently identified allergen (FIGURE A).¹⁰ Personal care products often are linked to ACD (FIGURE B). An analysis of data from the North American Contact Dermatitis Group revealed that the top 5 personal care product allergens were methylisothiazolinone (a preservative), fragrance mix I, balsam of Peru, quaternium-15 (a preservative), and paraphenylenediamine (PPD; a common component of hair dye) (FIGURE C).¹²

There is a paucity of epidemiologic data among various ethnic groups; however, a few studies have suggested that there is no difference in the frequency rates of positive patch test results in Black vs White populations.^11,13,14 One study of patch test results from 114 Black patients and 877 White patients at the Cleveland Clinic Foundation in Ohio demonstrated a similar allergy frequency of 43.0% and 43.6%, respectively.13 However, there were differences in the types of allergen sensitization. Black patients had higher positive patch test rates for PPD than White patients (10.6% vs 4.5%). Black men had a higher frequency of sensitivity to PPD (21.2% vs 4.2%) and imidazolidinyl urea (a formaldehyde-releasing preservative; 9.1% vs 2.6%) compared to White men.¹³

Continue to: Ethnicity and cultural practices...

Ethnicity and cultural practices influence epidemiologic patterns of ACD. Darker hair dyes used in Black patients¹⁴ and deeply pigmented PPD dye found in henna tattoos used in Indian and Black patients¹⁵ may lead to increased sensitization to PPD. ACD due to formaldehyde is more common in White patients, possibly due to more frequent use of formaldehyde-containing moisturizers, shampoos, and creams.¹⁵

Key clinical features in people with darker skin tones

In patients with SOC, the clinical features of ACD vary, posing a diagnostic challenge. Hyperpigmentation, lichenification, and induration are more likely to be seen than the papules, vesicles, and erythematous dermatitis often described in lighter skin tones or acute ACD. Erythema can be difficult to assess on darker skin and may appear violaceous or very faint pink.16

Worth noting

A high index of suspicion is necessary when interpreting patch tests in patients with SOC, as patch test kits use a reading plate with graduated intensities of erythema, papulation, and vesicular reactions to determine the likelihood of ACD. The potential contact allergens are placed on the skin on Day 1 and covered. Then, on Day 3 the allergens are removed. The skin is clinically evaluated using visual assessment and skin palpation. The reactions are graded as negative, irritant reaction, equivocal, weak positive, strong positive, or extreme reaction at around Days 3 and 5 to capture both early and delayed reactions.¹⁷ A patch test may be positive even if obvious signs of erythema are not appreciated as expected.

ACD is more common in women, with nickel being the most frequently identified allergen.

Adjusting the lighting in the examination room, including side lighting, or using a blue background can be helpful in identifying erythema in darker skin tones.^15,16,18 Palpation of the skin also is useful, as even slight texture changes and induration are indicators of a possible skin reaction to the test allergen.¹⁵

Health disparity highlight

Clinical photographs of ACD and patch test results in patients with SOC are not commonplace in the literature. Positive patch test results in patients with darker skin tones vary from those of patients with lighter skin tones, and if the clinician reading the patch test result is not familiar with the findings in darker skin tones, the diagnosis may be delayed or missed.¹⁵

Continue to: Furthermore, Scott et al...

Furthermore, Scott et al¹⁵ highlighted that many dermatology residency training programs have a paucity of SOC education in their curriculum. This lack of representation may contribute to the diagnostic challenges encountered by health care providers.

The lower rates of patch testing in Black patients are likely due to the impact of social determinants of health.

Timely access to health care and education as well as economic stability are essential for the successful management of patients with ACD. Some individuals with SOC have been disproportionately affected by social determinants of health. Rodriguez-Homs et al¹⁹ demonstrated that the distance needed to travel to a clinic and the poverty rate of the county the patient lives in play a role in referral to a clinician specializing in contact dermatitis.

A retrospective registry review of 2310 patients undergoing patch testing at the Massachusetts General Hospital in Boston revealed that 2.5% were Black, 5.5% were Latinx, 8.3% were Asian, and the remaining 83.7% were White.²⁰ Qian et al²¹ also looked at patch testing patterns among various sociodemographic groups (N = 1,107,530) and found that 69% of patients were White and 59% were female. Rates of patch testing among patients who were Black, lesser educated, male, lower income, and younger (children ages 0-12 years) were significantly lower than for other groups when ACD was suspected (P < .0001).²¹ The lower rates of patch testing in patients with SOC may be due to low suspicion of diagnosis, low referral rates due to limited medical insurance, and financial instability, as well as other socioeconomic factors.²⁰

Tamazian et al¹⁶ reviewed pediatric populations at 13 US centers and found that Black children received patch testing less frequently than White and Hispanic children. Another review of pediatric patch testing in patients with SOC found that a less comprehensive panel of allergens was used in this population.²²

The key to resolution of ACD is removal of the offending antigen, and if patients are not being tested, then they risk having a prolonged and complicated course of ACD with a poor prognosis. Patients with SOC also experience greater negative psychosocial impact due to ACD disease burden.^21,23 The lower rates of patch testing in Black patients cannot solely be attributed to difficulty diagnosing ACD in darker skin tones; it is likely due to the impact of social determinants of health. Alleviating health disparities will improve patient outcomes and quality of life.

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

Question: What doubles every 2 months and takes more than a decade and a half to reach its ultimate destination?

Answer: Medical knowledge. 

In 2011, researchers projected that by 2020, medical knowledge would double every 73 days. Also in 2011, investigators estimated that clinical research takes 17 years to translate from bench to bedside. 

This “fast-slow” paradox became more relevant than ever in 2020, when the coronavirus pandemic brought the world to a near standstill. Stakeholders in undergraduate, postgraduate, and continuing medical education (CME) were suddenly faced with choices that had been discussed theoretically but not yet applied on a wide scale: How do we deliver education if in-person instruction is not an option? 

Organized medicine and the clinical community made choices based on groundwork that had been laid prior to the pandemic. The medical community acted quickly out of necessity, implementing novel learning methods that are now being utilized and that need to be assessed in an ongoing manner. 

The Backdrop

Medical education has long been dominated by an in-person, didactic model anchored in teacher-centered, classroom-based learning. This design has been firmly entrenched for more than 100 years, since the publication of the Flexner report in 1910, which established the standard of 4 years of medical education. Prior to 2020, many experts acknowledged that alternative practices and emerging technologies should play a role in medical education, but indecision abounded, perhaps because there was no real-world catalyst for reform. Thus, despite various attempts, the adoption of alternative forms of teaching moved slowly. 

Pre-pandemic efforts

In 2017, the American Medication Association issued a report calling for “one of the most complete curricular reforms since the Flexner Report.” It urged leaders to “rethink nearly every facet of physician training,” including “greater emphasis on new technology.” The report also suggested a 14-month pre-rotation program focused on the core medical knowledge necessary to practice in a hospital setting, along with work in a primary care setting once every other week. 

Before the pandemic, “blended learning” (digital and live) and “flipped classroom” approaches were assessed. A meta-analysis comparing a blended learning format to traditional classroom model programs found that blended learning resulted in better knowledge outcomes. In the flipped classroom approach, non-classroom individual or group activities replace in-class instruction after pre-class self-preparation with provided resources. A meta-analysis of 28 comparative studies showed that the flipped classroom approach resulted in improved learning compared to traditional methods. Additionally, bite-sized learning approaches have been implemented and evaluated, showing improvement in immediate knowledge recall. 

Barriers to widespread implementation

Despite the need to increase medical knowledge dissemination and implement approaches proven to do so effectively, barriers to adoption are well documented. Obstacles include time limitations, inadequate technical skills, insufficient infrastructure, and a wide variety in and range of expertise of both learners and institutional strategies. There are also differences in effective techniques for teaching various topics based on the content. Some topics require knowledge-based training, whereas others fall more easily into skills-based training. 

Additionally, when it comes to new evidence that needs to be translated to clinical evaluation and delivery, there is ongoing debate about the established peer-review process, which is rigorous but time-consuming vs the open-access publication process, which can disseminate information more quickly but is prone to error. 

Proposed solutions

Proposed solutions to these barriers include improving educator skills, offering incentives for innovative content development, cultivating better institutional strategies, and achieving buy-in from all stakeholders. Also important is thoughtful adaptation of content to various electronic formats, such as audiovisual presentation of educational material, social media content, and gamification of content, as well as ongoing assessment of both education delivery and consumption—followed by rapid pivoting when necessary. 

Despite these clearly identified challenges and thoughtful solutions, change was relatively slow until March 2020. 

The Trigger

With medical knowledge expanding so rapidly, imagine if medical education moved slowly or came to a complete halt when a worldwide pandemic was declared, the effects would have been catastrophic. COVID pushed organized medicine and the healthcare community to accelerate the adoption of novel technological approaches to keep the medical knowledge pipeline flowing at a relatively reasonable— if not ideal—rate. 

Challenges the pandemic produced, along with potential mitigation strategies, are outlined below.      

Economic consequences: The pandemic resulted in lost income for training programs and decreased funding for graduate medical education.

Possible solution: Creating budget allowances to adopt new technologies

Impact on diversity, equity, and inclusion: COVID-19 amplified existing implicit and explicit biases in society, particularly in the field of medicine. Women trainees and individuals from disadvantaged backgrounds were disproportionately impacted.

Possible solution: Creating programs that increase awareness of the subtle nature of implicit bias and the outsized impact it can have on certain segments of the population, and offering resources to mitigate stressors such as childcare and access to technology solutions

Impact on mental health and wellness: Working through the pandemic was challenging professionally, and the pandemic also exposed individuals to stigma, loneliness, and behavioral health issues (eg, mood and sleeping disorders), which created challenges in personal lives as well. These challenges lasted well over 2 years and have a clear ongoing impact.  

Possible solution: Providing accessible behavioral health resources, regularly assessing and addressing burnout, and regularly cycling trainees off of high-intensity rotations

Education delivery challenges: The sudden cancellation of in-person classes and training, from medical school lectures to rotations, created uncertainty. In-person rounds and bedside learning were significantly restricted. Moreover, as the need to perform clinical duties during the pandemic increased, time for teaching decreased. Some areas were more heavily impacted than others (eg, instruction around elective surgeries, outpatient medicine, and non-critical care training). 

Possible solution: Digitizing education delivery and developing other innovative methods to compensate for a lack of face-to-face instruction

Sudden need for rapid information dissemination: The limits of traditional peer review were tested during the pandemic. Managing individuals infected with the novel coronavirus created a situation where the clinical community needed scientific information quickly, increasing the risk of misinformation. 

Possible solution: Disseminating information as quickly as possible by leveraging public-private partnerships and government investment in high-quality science while maintaining peer review integrity to ensure rigorous evaluation

The Evidence

Early evidence is emerging about efforts undertaken during the pandemic to maintain adequate levels of preclinical learning, clinical training, and CME. 

Preclinical learning: Virtual formats are generally accepted, and interactive discussion is preferred. But be aware of potential stressors.

A cross-sectional study involving 173 histology and pathology students at European University Cyprus found that preclinical medical education is possible via virtual learning. The pandemic forced respondents to adapt immediately to emergency remote teaching. Survey results found the concept was generally well accepted, though some stressors (eg, poor internet connection) impacted perception. Most histology and pathology students (58% and 68%, respectively) said they would prefer blended learning in the future, compared with all-live (39% and 28%, respectively), or all-virtual (4% and 5%, respectively) classrooms. 

In a systematic review of 13 studies that compared digital learning with live classroom education for medical and nursing students, investigators from China found that standalone digital models are as effective as conventional modalities for improving knowledge and practice. Moreover, students preferred interactive discussion to a straight lecture format when participating online. 

Clinical training: Virtual clerkships work, but a blended approach seems preferable.

In a study involving 16 third-year medical students in the general surgery clerkship at Cleveland Clinic, respondents reported their experience before and after participating in a case-based virtual surgery clerkship program. Students were significantly more confident that they could independently assess a surgical consult after taking the course. Average scores of curriculum-based surgical knowledge increased as well. 

In an assessment of alternative approaches to clinical clerkships involving 42 students, investigators from China evaluated the impact of using simulated electronic health records (EHRs) for inpatient training and electronic problem-based learning and virtual interviews for outpatient training. Students using simulated EHRs felt it improved their ability to write in and summarize the record. Those who participated in electronic problem-based learning and virtual interviewing said their interviewing and counseling skills improved. However, students also noted traditional clinical clerkships are better for certain types of learning, suggesting that a blended approach is preferred. 

CME: Virtual CME is accepted and improves performance, but barriers remain, including a preference for face-to-face networking.

Researchers reviewed 2,007 post-activity responses from clinicians who participated in online CME at a South Korean hospital. Of the 1332 participants who reported their satisfaction level, 85% reported being satisfied with the format and content. Among all respondents, nearly 9 in 10 said that the content would influence the way they practice. Of the 611 participants who responded to a follow-up survey 3 months later, 78% said they made changes in their clinical practice based on what they learned. 

However, many clinicians prefer in-person CME. A Canadian-based memory clinic held 5 interprofessional education sessions and reported on participant experience; 3 of the sessions occurred live before March 2020 and 2 were held via videoconference once the pandemic was declared. Ratings of satisfaction, relevance, knowledge acquisition, and knowledge application were similar in both groups, but the virtual sessions were rated as less enjoyable and lacking in networking opportunities. In-person learning was preferred. 

Primary care clinicians in Portugal evaluated a CME digital platform and reported several barriers, including time constraints, perceived excessive work, lack of digital competence, lack of motivation, and emotional factors.      

The Future
Although challenges remain, changes due to the pandemic have been implemented in medical training and have shown preliminary success in certain domains. Medical education is rapidly evolving, and as we move further from the pandemic, diligent ongoing evaluation is needed to assess the best use of technology and various innovative teaching modalities. Keeping medical education learner-centered and instituting timely course correction if certain modalities of knowledge/skill delivery are found to be ineffective will be key to ensuring the robustness of training for future generations.   

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

VMS, also known as hot flashes, night sweats, or cold sweats, occur for the majority of perimenopausal and menopausal women.¹ In one study, the mean duration of clinically significant VMS was 5 years, and one-third of participants continued to have bothersome hot flashes 10 or more years after the onset of menopause.² VMS may contribute to disrupted sleep patterns and depressed mood.³

All obstetrician-gynecologists know that estradiol and other estrogens are highly effective in the treatment of bothersome VMS. A meta-analysis reported that the frequency of VMS was reduced by 60% to 80% with oral estradiol (1 mg/day), transdermal estradiol(0.05 mg/day), and conjugated estrogen (0.625 mg).⁴ Breast tenderness and irregular uterine bleeding are common side effects of estrogen treatment of VMS. Estrogen treatment is contraindicated in patients with estrogen-responsive cancers, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, and some cases of inherited thrombophilia. For these patients, an important option is the nonhormonal treatment of VMS, and several nonhormonal medications have been demonstrated to be effective therapy (TABLE 1). In this editorial I will review the medication treatment of VMS with escitalopram, paroxetine, gabapentin, and fezolinetant.

Escitalopram and paroxetine

Escitalopram and paroxetine have been shown to reduce VMS more than placebo in multiple clinical trials.^5-10 In addition, escitalopram and paroxetine, at the doses tested, may be more effective for the treatment of VMS than sertraline, citalopram, or fluoxetine.¹¹ In one trial assessing the efficacy of escitalopram to treat VMS, 205 patients with VMS were randomly assigned to 8 weeks of treatment with placebo or escitalopram.⁵ The initial escitalopram dose was 10 mg daily. At week 4:

• if VMS frequency was reduced by ≥ 50%, the patient remained on the 10-mg dose
• if VMS frequency was reduced by < 50%, the escitalopram dose was increased to 20 mg daily.

Following 8 weeks of treatment, the frequency of VMS decreased for patients in the placebo and escitalopram groups by 33% and 47%, respectively. Similar results have been reported in other studies.⁶

Paroxetine at a dose of 7.5 mg/day administered at bedtime is approved by the US Food and Drug Administration (FDA) for the treatment of VMS. In a pivotal study, 1,112 patients with VMS were randomly assigned to receive a placebo or paroxetine 7.5 mg at bedtime.⁹ In the 12-week study the reported decrease in mean weekly frequency of VMS for patients in the placebo and paroxetine groups were -37 and -44, respectively.⁹ Paroxetine 7.5 mg also reduced awakenings per night attributed to VMS and increased nighttime sleep duration.¹⁰

Depressed mood is prevalent among perimenopausal and postmenopausal patients.¹² Prescribing escitalopram or paroxetine for VMS also may improve mood. Venlafaxine and desvenlafaxine are effective for the treatment of VMS;^13,14 however, I seldom prescribe these medications for VMS because in my experience they are associated with more bothersome side effects, including dry mouth, decreased appetite, nausea, and insomnia than escitalopram or low-dose paroxetine.

Continue to: Gabapentin...

Gabapentin

Numerous randomized clinical trials have reported that gabapentin is superior to placebo for the treatment of VMS.¹⁵ In one trial, 420 patients with breast cancer and VMS were randomly assigned to 8 weeks of treatment with placebo, gabapentin 300 mg/day (G300), or gabapentin 900 mg/day (G900) in 3 divided doses.¹⁶ Following 8 weeks of treatment, reduction in hot-flash severity score among patients receiving placebo, G300, or G900 was 15%, 31%, and 46%, respectively. Fatigue and somnolence were reported more frequently among patients taking gabapentin 900 mg/day. In a small trial, 60 patients with VMS were randomized to receive placebo, conjugated estrogen (0.2625 mg/day),or gabapentin (target dose of 2,400 mg/day in 3 divided doses).¹⁷ Following 12 weeks of treatment, the patient-reported decrease in VMS for those taking placebo, estrogen, or gabapentin was 54%, 72%, and 71%, respectively.

High-dose gabapentin treatment was associated with side effects of headache and dizziness more often than placebo or estrogen. Although gabapentin is not a treatment for insomnia, in my practice if a menopausal patient has prominent and bothersome symptoms of sleep disturbance and mild VMS symptoms, I will consider a trial of low-dose gabapentin. Some experts recommend initiating gabapentin at a dose of 100 mgdaily before bedtime to assess the effectiveness of a low dose that seldom causes significant side effects.

ILLUSTRATION: ZONDA/ZAZA STUDIO/SHUTTERSTOCK

Fezolinetant

In a study of genetic variation associated with VMS, investigators discovered that nucleic acid variation in the neurokinin 3 (NK3) receptor was strongly associated with the prevalence of VMS, suggesting that this receptor is in the causal pathway to menopausal VMS.¹⁸ Additional research demonstrated that the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are involved in the control of hypothalamic thermoregulation, are stimulated by neurokinin B, acting through the NK3 receptor, and suppressed by estradiol. A reduction in hypothalamic estrogen results in unopposed neurokinin B activity, which stimulates KNDy neurons, destabilizing the hypothalamic thermoregulatory center, causing vasodilation, which is perceived as hot flashes and sweating followed by chills.¹⁹

Fezolinetant is a high-affinity NK3 receptor antagonist that blocks the activity of neurokinin B, stabilizing the hypothalamic thermoregulatory center, thereby suppressing hot flashes. It is approved by the FDA for the treatment of moderate to severe VMS due to menopause using a fixed dose of 45 mg daily.²⁰ In one clinical trial, 500 menopausal patients with bothersome VMS were randomly assigned to 12 weeks of treatment with placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day. Following 12 weeks of treatment, the reported frequency rates of VMS among patients in the placebo, F30, and F45 groups were reduced by 43%, 61%, and 64%, respectively.²¹ In addition, following 12 weeks of treatment, the severity of VMS rates among patients in the placebo, F30, and F45 groups were reduced by 20%, 26%, and 32%, respectively.

Fezolinetant improved the quality of sleep and was associated with an improvement in patient-reported quality of life. Following 12 weeks of treatment, sleep quality among patients in the placebo, F30, and F45 groups was reported to be “much or moderately better” in 34%, 45%, and 54% of the patients, respectively.²¹ Similar results were reported in a companion study.²²

Fezolinetant is contraindicated for patients with liver cirrhosis or severe renal impairment (estimated glomerular filtration rate of < 30 mL/min/1.73 m2). Before initiating treatment, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin (total and direct). Fezolinetant should not be prescribed if any of these tests are greater than twice the upper limit of normal. These tests should be repeated at 3, 6, and 9 months, and if the patient reports symptoms or signs of liver injury (nausea, vomiting, jaundice). Fezolinetant is metabolized by CYP1A2 and should not be prescribed to patients taking strong CYP1A2 inhibitors. The most common side effects associated with fezolinetant treatment are abdominal pain (4.3%), diarrhea (3.9%), insomnia (3.9%), back pain (3.0%), and hepatic transaminase elevation (2.3%). Fezolinetant has not been thoroughly evaluated in patients older than age 65. Following an oral dose of the medication, the median maximum concentration is reached in 1.5 hours, and the half-life is estimated to be 10 hours.²⁰ Of all the medications discussed in this editorial, fezolinetant is the most expensive.

Effective VMS treatment improves overall health

Estrogen therapy is the gold standard treatment of VMS. However, many menopausal patients with bothersome VMS prefer not to take estrogen, and some have a medical condition that is a contraindication to estrogen treatment. The nonhormonal medication options for the treatment of VMS include escitalopram, paroxetine, gabapentin, and fezolinetant. Patients value the ability to choose the treatment they prefer, among all available hormonal and nonhormonal medication options. For mid-life women, effectively treating bothersome VMS is only one of many interventions that improves health. Optimal health is best achieved with²³:

• high-quality diet
• daily physical activity
• appropriate body mass index
• nicotine avoidance
• a healthy sleep schedule
• normal blood pressure, lipid, and glucose levels.

Women who have a high-quality diet; daily physical activity; an appropriate body mass index; and normal blood pressure, cholesterol, and glucose levels are estimated to live 9 disease-free years longer than other women.²⁴ ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.

ILLUSTRATIVE CASE

A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.

The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?

Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.²The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).³

Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, ⁴ the Eighth Joint National Committee (JNC 8), ⁵ the International Society of Hypertension, ⁶ and the European Society of Cardiology ⁷ use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. ⁸

When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the Dietary Approaches to Stop Hypertension (DASH) diet. Other lifestyle modifications include weight loss, tobacco cessation, reduced daily alcohol intake, and increased physical activity. ⁹

Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. ^10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. ¹³ Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of ­patient-oriented evidence that demonstrates improvement in CV disease and mortality.

The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. ¹⁴ Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. ¹³

Continue to: In this 2022 systematic review...

In this 2022 systematic review and meta-analysis, ¹ Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-­randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.

STUDY SUMMARY

Salt substitutes reduced BP across diverse populations

This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of ­potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.

The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.

The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I ² > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.

Consistent reduction in BP and clinical outcomes across diverse populations and regions suggests potential worldwide benefit from the use of potassium-enriched salt in appropriate patients.

Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was ­associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.

Continue to: Only 2 of the studes...

Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.

WHAT’S NEW

High-quality data demonstrate beneficial outcomes

Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that ­potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.

CAVEATS

Some patient populations, comorbidities excluded from study

The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.

Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.

CHALLENGES TO IMPLEMENTATION

For appropriate patients, no challenges anticipated

There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-­sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.