A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.

“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.

The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).

The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.

Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.

After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.

Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.

One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.

“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.

No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.

SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.

A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.

“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.

The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).

The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.

Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.

After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.

Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.

One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.

“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.

No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.

SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.

A comparative cost analysis suggests single-fraction spine stereotactic radiosurgery is associated with lower total resource utilization among other radiation therapy (RT) options, according to recent research.

“We quantified institutional costs associated with RT for spinal metastases, using a time-driven activity-based costing model,” wrote David Boyce-Fappiano, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. Their report is in the Journal of Oncology Practice.

The researchers compared resource utilization across four common RT regimens: single-fraction spine stereotactic radiosurgery (to 18 Gy), 3-fraction spine stereotactic radiosurgery (to 27 Gy), 10-fraction three-dimensional RT (3D-RT) (to 30 Gy), and 10-fraction intensity-modulated RT (IMRT) (to 30 Gy).

The analysis framework involved the creation of both process maps and process times, which included a detailed outline to map the complete clinical care process, while expert panel interviews were used to establish process times.

Other measures, such as the capacity cost rate, were calculated for each resource, and subsequently used to estimate total costs.

After analysis, the researchers found that across the four RT regimens, full-cycle care costs for single-fraction spine stereotactic radiosurgery were 17% less and 17% more than IMRT and 3D-RT, respectively. However, technical costs for IMRT were 50% and 77% more than 3-fraction and single-fraction SSRS, respectively.

Overall, the analysis “supports the institutional resource efficiency of single-fraction stereotactic radiosurgery for spinal metastases,” Dr. Boyce-Fappiano and associates said.

One key limitation of the analysis was the single-center design of the study. As a result, the findings may not be applicable to all clinical settings.

“Additional research can incorporate these data alongside toxicity and retreatment rates to evaluate the long-term cost effectiveness of spine stereotactic radiosurgery over a full cycle of care,” they concluded.

No funding sources were reported in the manuscript. The authors reported financial affiliations with AbbVie, AstraZeneca, Boston Scientific, Bristol-Myers Squibb BTG, Coleman Consulting, US Oncology, Oscar Health, RefleXion Medical, and several others.

SOURCE: Boyce-Fappiano D et al. J Oncol Pract. 2019 Nov 25. doi: 10.1200/JOP.19.00480.

EVIDENCE SUMMARY

A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.¹ It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.

Further studies also support a link between e-cigarette and cigarette use

Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).^2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).² A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.³ A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).⁴ A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-­dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.⁵

RECOMMENDATIONS

A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.⁶ It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).

Editor’s takeaway

While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.

EVIDENCE SUMMARY

A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.¹ It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.

Further studies also support a link between e-cigarette and cigarette use

Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).^2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).² A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.³ A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).⁴ A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-­dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.⁵

RECOMMENDATIONS

A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.⁶ It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).

Editor’s takeaway

While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.

EVIDENCE SUMMARY

A meta-analysis of 9 prospective cohort studies (total 17,389 patients) at least 6 months in duration evaluated the association between e-cigarette exposure and subsequent cigarette smoking in adolescents and young adults.¹ It found that smoking was more prevalent in ever-users of e-cigarettes than nonusers at 1 year (23.3% vs 7.2%; odds ratio [OR] = 3.5; 95% confidence interval [CI], 2.38-5.16). The association was even stronger among recent users (within 30 days) of e-cigarettes compared with nonusers (21.5% vs 4.6%; OR = 4.28; 95% CI, 2.52-7.27). The mean age of approximately 80% of participants was 20 years or younger.

Further studies also support a link between e-cigarette and cigarette use

Four subsequent cohort studies also found links between e-cigarette exposure and any level of cigarette smoking (TABLE).^2-5 A Canadian study of high school students reported a positive association between recent e-cigarette use (within the previous 30 days) and subsequent daily cigarette usage (OR = 1.79; 95% CI, 1.41-2.28).² A British study that documented the largest association uniquely validated smoking status with carbon monoxide testing.³ A study of Mexican adolescents found that adolescents who tried e-cigarettes were more likely to smoke cigarettes and also reported an association between e-cigarette use and marijuana use (relative risk [RR] = 1.93; 95% CI, 1.14–3.28).⁴ A California study that evaluated e-cigarette nicotine level and subsequent cigarette smoking found a dose-­dependent response, suggesting an association between nicotine concentration and subsequent uptake of cigarettes.⁵

RECOMMENDATIONS

A policy statement from The American Academy of Pediatrics Section on Tobacco Control states that youth who use e-cigarettes are more likely to use cigarettes and other tobacco products.⁶ It recommends that physicians screen patients for use of electronic nicotine delivery systems (ENDS), counsel about immediate and long-term harms and the importance of not using ENDS, and offer current users tobacco cessation counseling (with Food and Drug Administration-approved tobacco dependence treatment).

Editor’s takeaway

While these cohort studies don’t definitively prove causation, they provide the best quality evidence that we are likely to see in support of counseling adolescents against using e-cigarettes, educating them about harms, and offering tobacco cessation measures when appropriate.

A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

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

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]