Recent guidelines from the United States Preventive Services Task Force (USPSTF) say that there is insufficient evidence to recommend screening for obstructive sleep apnea in people who have no symptoms of it.^1–3

The USPSTF committee systematically reviewed the evidence, sifting through 1,315 articles,³ and found no randomized controlled trials that compared screening with no screening in adults who have no symptoms (or no recognized symptoms) of obstructive sleep apnea. Conclusion: “The current evidence is insufficient to assess the balance of benefits and harms of screening for [obstructive sleep apnea] in asymptomatic adults.”¹

This is logical, rigorous, and evidence-based. However, the conclusions might be misinterpreted and need to be put into context.

SCREENING IS WARRANTED IF PATIENTS HAVE SYMPTOMS

First, note that the USPSTF is referring to people who have no symptoms. The American Academy of Sleep Medicine has issued recommendations about screening and diagnostic testing in people who do have symptoms,⁴ in whom it is important to pursue screening and diagnostic testing.

Symptoms of obstructive sleep apnea include excessive daytime sleepiness, fatigue, drowsy driving, disrupted or fragmented sleep, nocturia, witnessed apnea, snoring, restless sleep, neurocognitive deficits, and depressed mood. Treating it improves these symptoms, as clinical trials have shown unequivocally and consistently.⁵

Moreover, the third edition of the International Classification of Sleep Disorders defines obstructive sleep apnea as an obstructive apnea-hypopnea index of 15 or more events per hour even in the absence of symptoms. This threshold recognizes the risk of adverse health outcomes observed in population-based studies (ie, in participants recruited irrespective of symptoms).⁶

ABSENCE OF EVIDENCE, NOT EVIDENCE OF ABSENCE

Second, the absence of sufficient evidence cited by the USPSTF does not necessarily mean that screening for obstructive sleep apnea in asymptomatic people is not beneficial—it has just not been systematically studied. There was insufficient evidence available to make a recommendation to allocate resources to screen all patients irrespective of symptoms.

The Sleep Heart Health Study suggested that few people with obstructive sleep apnea were diagnosed with it and that even fewer were treated for it.⁷ More recent data indicate that this underdiagnosis persists and is more pervasive in underserved minority groups.^8,9

SCREENING VS CASE-FINDING

Moreover, screening is not the same as case-finding. The purpose of screening, as defined 50 years ago by Wilson and Jungner in a report for the World Health Organization, is “to discover those among the apparently well who are in fact suffering from disease.”¹⁰

Case-finding, on the other hand, focuses on those suspected of being at risk of the disease. In the case of obstructive sleep apnea, this is a lot of people. The overall prevalence of obstructive sleep apnea is about 26% by one estimate,¹¹ and many more people have risk factors for it. For example, in one study, 69% of patients presenting to a primary care clinic were overweight or obese,¹² and many primary care patients have diseases that obstructive sleep apnea can exacerbate. One can therefore argue that in clinical practice, testing for obstructive sleep apnea is more like case-finding than screening—most patients that you see have unrecognized symptoms of it or risk factors for it.

Principles for screening outlined by Wilson and Jungner¹⁰ were:

• The condition we are trying to detect should be important
• There should be an accepted treatment for it
• Facilities for diagnosis and treatment should be available
• Testing should be acceptable to the population
• There should be cost benefit to the expense of case-finding
• There should be an agreed-upon policy on whom to treat as patients.

Screening for obstructive sleep apnea meets many of these criteria.

Obstructive sleep apnea is important

Solid evidence exists that obstructive sleep apnea exerts a bad effect on health and quality of life. Population-based studies that enrolled participants irrespective of symptoms indicate that the risk of death is about twice as high in those with severe obstructive sleep apnea as in those without, and treatment exerts benefit especially in those with cardiovascular risk.^13,14 Therefore, the criterion for screening that says the disease must be important is met.

Pathophysiologic pathways by which obstructive sleep apnea causes harm include intermittent hypoxia, hypercapnia, intrathoracic pressure swings, and autonomic nervous system fluctuations. 

Treatment is beneficial

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recognized obstructive sleep apnea as a cause of hypertension.¹⁵

Treating obstructive sleep apnea lowers blood pressure, which in turn improves cardio­vascular outcomes. Effects are most pronounced in those with resistant hypertension. The reduction in blood pressure is only about 2 to 3 mm Hg, but this translates to a 4% to 8% reduction in future risk of stroke and coronary heart disease.^16,17

The Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease multicenter randomized clinical trial investigated the impact of treating obstructive sleep apnea with continuous positive airway pressure (CPAP) compared with usual care.¹⁸ Although no statistically significant difference was seen in the composite cardiovascular outcome, propensity-score analysis in the subgroup adherent to CPAP demonstrated a lower composite of cerebral events in those who used CPAP for at least 4 hours a day.

The findings from this trial are difficult to interpret for several reasons. Adherence to CPAP was suboptimal, the severity of obstructive sleep apnea might not have been bad enough to permit observation of a significant treatment effect, and the generalizability of the findings is unclear, given that many of the participants were from underresourced regions.¹⁹

In a meta-analysis of cohort studies comprising more than 3 million participants, Fu et al found that the cardiovascular mortality rate was 63% lower in those with obstructive sleep apnea using CPAP than in untreated patients.²⁰

APPLY CLINICAL JUDGMENT

Overall, the USPSTF report is intended to guide healthcare decision-makers. However, it includes a caveat to not substitute the findings for clinical judgment and to interpret the findings in the context of collateral pertinent information.²

Although no high-quality data exist to support or refute global screening for obstructive sleep apnea in the primary care setting, the high prevalence of this disease and its detrimental effects on health and quality of life if left untreated should not be dismissed.

Arguably, most patients who present to primary care clinics are not healthy, are not free of symptoms, and are at risk of obstructive sleep apnea because they are obese. Testing for it is therefore more like case-finding than screening.

In view of the serious consequences of obstructive sleep apnea, we should view the situation as an opportunity to examine the impact of screening. Perhaps using electronic medical records, we could collect sleep-specific measures, implement case-finding strategies, and perform pragmatic clinical trials to inform and guide optimal and cost-effective screening approaches.

Patients with common disorders such as obstructive sleep apnea are often considered asymptomatic until asked about symptoms. Therefore, careful review of systems incorporating sleep health is important, particularly as patients do not typically volunteer this information. Obtaining this history does not necessarily fall under the USPSTF’s recommendation not to screen.

Future efforts should focus on leveraging the electronic medical record platform to collect sleep-specific measures, implementing case-finding strategies, and performing pragmatic clinical trials in the primary care setting to inform and guide optimal and cost-effective approaches to screening.

Recent guidelines from the United States Preventive Services Task Force (USPSTF) say that there is insufficient evidence to recommend screening for obstructive sleep apnea in people who have no symptoms of it.^1–3

The USPSTF committee systematically reviewed the evidence, sifting through 1,315 articles,³ and found no randomized controlled trials that compared screening with no screening in adults who have no symptoms (or no recognized symptoms) of obstructive sleep apnea. Conclusion: “The current evidence is insufficient to assess the balance of benefits and harms of screening for [obstructive sleep apnea] in asymptomatic adults.”¹

This is logical, rigorous, and evidence-based. However, the conclusions might be misinterpreted and need to be put into context.

SCREENING IS WARRANTED IF PATIENTS HAVE SYMPTOMS

First, note that the USPSTF is referring to people who have no symptoms. The American Academy of Sleep Medicine has issued recommendations about screening and diagnostic testing in people who do have symptoms,⁴ in whom it is important to pursue screening and diagnostic testing.

Symptoms of obstructive sleep apnea include excessive daytime sleepiness, fatigue, drowsy driving, disrupted or fragmented sleep, nocturia, witnessed apnea, snoring, restless sleep, neurocognitive deficits, and depressed mood. Treating it improves these symptoms, as clinical trials have shown unequivocally and consistently.⁵

Moreover, the third edition of the International Classification of Sleep Disorders defines obstructive sleep apnea as an obstructive apnea-hypopnea index of 15 or more events per hour even in the absence of symptoms. This threshold recognizes the risk of adverse health outcomes observed in population-based studies (ie, in participants recruited irrespective of symptoms).⁶

ABSENCE OF EVIDENCE, NOT EVIDENCE OF ABSENCE

Second, the absence of sufficient evidence cited by the USPSTF does not necessarily mean that screening for obstructive sleep apnea in asymptomatic people is not beneficial—it has just not been systematically studied. There was insufficient evidence available to make a recommendation to allocate resources to screen all patients irrespective of symptoms.

The Sleep Heart Health Study suggested that few people with obstructive sleep apnea were diagnosed with it and that even fewer were treated for it.⁷ More recent data indicate that this underdiagnosis persists and is more pervasive in underserved minority groups.^8,9

SCREENING VS CASE-FINDING

Moreover, screening is not the same as case-finding. The purpose of screening, as defined 50 years ago by Wilson and Jungner in a report for the World Health Organization, is “to discover those among the apparently well who are in fact suffering from disease.”¹⁰

Case-finding, on the other hand, focuses on those suspected of being at risk of the disease. In the case of obstructive sleep apnea, this is a lot of people. The overall prevalence of obstructive sleep apnea is about 26% by one estimate,¹¹ and many more people have risk factors for it. For example, in one study, 69% of patients presenting to a primary care clinic were overweight or obese,¹² and many primary care patients have diseases that obstructive sleep apnea can exacerbate. One can therefore argue that in clinical practice, testing for obstructive sleep apnea is more like case-finding than screening—most patients that you see have unrecognized symptoms of it or risk factors for it.

Principles for screening outlined by Wilson and Jungner¹⁰ were:

• The condition we are trying to detect should be important
• There should be an accepted treatment for it
• Facilities for diagnosis and treatment should be available
• Testing should be acceptable to the population
• There should be cost benefit to the expense of case-finding
• There should be an agreed-upon policy on whom to treat as patients.

Screening for obstructive sleep apnea meets many of these criteria.

Obstructive sleep apnea is important

Solid evidence exists that obstructive sleep apnea exerts a bad effect on health and quality of life. Population-based studies that enrolled participants irrespective of symptoms indicate that the risk of death is about twice as high in those with severe obstructive sleep apnea as in those without, and treatment exerts benefit especially in those with cardiovascular risk.^13,14 Therefore, the criterion for screening that says the disease must be important is met.

Pathophysiologic pathways by which obstructive sleep apnea causes harm include intermittent hypoxia, hypercapnia, intrathoracic pressure swings, and autonomic nervous system fluctuations. 

Treatment is beneficial

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recognized obstructive sleep apnea as a cause of hypertension.¹⁵

Treating obstructive sleep apnea lowers blood pressure, which in turn improves cardio­vascular outcomes. Effects are most pronounced in those with resistant hypertension. The reduction in blood pressure is only about 2 to 3 mm Hg, but this translates to a 4% to 8% reduction in future risk of stroke and coronary heart disease.^16,17

The Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease multicenter randomized clinical trial investigated the impact of treating obstructive sleep apnea with continuous positive airway pressure (CPAP) compared with usual care.¹⁸ Although no statistically significant difference was seen in the composite cardiovascular outcome, propensity-score analysis in the subgroup adherent to CPAP demonstrated a lower composite of cerebral events in those who used CPAP for at least 4 hours a day.

The findings from this trial are difficult to interpret for several reasons. Adherence to CPAP was suboptimal, the severity of obstructive sleep apnea might not have been bad enough to permit observation of a significant treatment effect, and the generalizability of the findings is unclear, given that many of the participants were from underresourced regions.¹⁹

In a meta-analysis of cohort studies comprising more than 3 million participants, Fu et al found that the cardiovascular mortality rate was 63% lower in those with obstructive sleep apnea using CPAP than in untreated patients.²⁰

APPLY CLINICAL JUDGMENT

Overall, the USPSTF report is intended to guide healthcare decision-makers. However, it includes a caveat to not substitute the findings for clinical judgment and to interpret the findings in the context of collateral pertinent information.²

Although no high-quality data exist to support or refute global screening for obstructive sleep apnea in the primary care setting, the high prevalence of this disease and its detrimental effects on health and quality of life if left untreated should not be dismissed.

Arguably, most patients who present to primary care clinics are not healthy, are not free of symptoms, and are at risk of obstructive sleep apnea because they are obese. Testing for it is therefore more like case-finding than screening.

In view of the serious consequences of obstructive sleep apnea, we should view the situation as an opportunity to examine the impact of screening. Perhaps using electronic medical records, we could collect sleep-specific measures, implement case-finding strategies, and perform pragmatic clinical trials to inform and guide optimal and cost-effective screening approaches.

Patients with common disorders such as obstructive sleep apnea are often considered asymptomatic until asked about symptoms. Therefore, careful review of systems incorporating sleep health is important, particularly as patients do not typically volunteer this information. Obtaining this history does not necessarily fall under the USPSTF’s recommendation not to screen.

Future efforts should focus on leveraging the electronic medical record platform to collect sleep-specific measures, implementing case-finding strategies, and performing pragmatic clinical trials in the primary care setting to inform and guide optimal and cost-effective approaches to screening.

Recent guidelines from the United States Preventive Services Task Force (USPSTF) say that there is insufficient evidence to recommend screening for obstructive sleep apnea in people who have no symptoms of it.^1–3

The USPSTF committee systematically reviewed the evidence, sifting through 1,315 articles,³ and found no randomized controlled trials that compared screening with no screening in adults who have no symptoms (or no recognized symptoms) of obstructive sleep apnea. Conclusion: “The current evidence is insufficient to assess the balance of benefits and harms of screening for [obstructive sleep apnea] in asymptomatic adults.”¹

This is logical, rigorous, and evidence-based. However, the conclusions might be misinterpreted and need to be put into context.

SCREENING IS WARRANTED IF PATIENTS HAVE SYMPTOMS

First, note that the USPSTF is referring to people who have no symptoms. The American Academy of Sleep Medicine has issued recommendations about screening and diagnostic testing in people who do have symptoms,⁴ in whom it is important to pursue screening and diagnostic testing.

Symptoms of obstructive sleep apnea include excessive daytime sleepiness, fatigue, drowsy driving, disrupted or fragmented sleep, nocturia, witnessed apnea, snoring, restless sleep, neurocognitive deficits, and depressed mood. Treating it improves these symptoms, as clinical trials have shown unequivocally and consistently.⁵

Moreover, the third edition of the International Classification of Sleep Disorders defines obstructive sleep apnea as an obstructive apnea-hypopnea index of 15 or more events per hour even in the absence of symptoms. This threshold recognizes the risk of adverse health outcomes observed in population-based studies (ie, in participants recruited irrespective of symptoms).⁶

ABSENCE OF EVIDENCE, NOT EVIDENCE OF ABSENCE

Second, the absence of sufficient evidence cited by the USPSTF does not necessarily mean that screening for obstructive sleep apnea in asymptomatic people is not beneficial—it has just not been systematically studied. There was insufficient evidence available to make a recommendation to allocate resources to screen all patients irrespective of symptoms.

The Sleep Heart Health Study suggested that few people with obstructive sleep apnea were diagnosed with it and that even fewer were treated for it.⁷ More recent data indicate that this underdiagnosis persists and is more pervasive in underserved minority groups.^8,9

SCREENING VS CASE-FINDING

Moreover, screening is not the same as case-finding. The purpose of screening, as defined 50 years ago by Wilson and Jungner in a report for the World Health Organization, is “to discover those among the apparently well who are in fact suffering from disease.”¹⁰

Case-finding, on the other hand, focuses on those suspected of being at risk of the disease. In the case of obstructive sleep apnea, this is a lot of people. The overall prevalence of obstructive sleep apnea is about 26% by one estimate,¹¹ and many more people have risk factors for it. For example, in one study, 69% of patients presenting to a primary care clinic were overweight or obese,¹² and many primary care patients have diseases that obstructive sleep apnea can exacerbate. One can therefore argue that in clinical practice, testing for obstructive sleep apnea is more like case-finding than screening—most patients that you see have unrecognized symptoms of it or risk factors for it.

Principles for screening outlined by Wilson and Jungner¹⁰ were:

• The condition we are trying to detect should be important
• There should be an accepted treatment for it
• Facilities for diagnosis and treatment should be available
• Testing should be acceptable to the population
• There should be cost benefit to the expense of case-finding
• There should be an agreed-upon policy on whom to treat as patients.

Screening for obstructive sleep apnea meets many of these criteria.

Obstructive sleep apnea is important

Solid evidence exists that obstructive sleep apnea exerts a bad effect on health and quality of life. Population-based studies that enrolled participants irrespective of symptoms indicate that the risk of death is about twice as high in those with severe obstructive sleep apnea as in those without, and treatment exerts benefit especially in those with cardiovascular risk.^13,14 Therefore, the criterion for screening that says the disease must be important is met.

Pathophysiologic pathways by which obstructive sleep apnea causes harm include intermittent hypoxia, hypercapnia, intrathoracic pressure swings, and autonomic nervous system fluctuations. 

Treatment is beneficial

The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recognized obstructive sleep apnea as a cause of hypertension.¹⁵

Treating obstructive sleep apnea lowers blood pressure, which in turn improves cardio­vascular outcomes. Effects are most pronounced in those with resistant hypertension. The reduction in blood pressure is only about 2 to 3 mm Hg, but this translates to a 4% to 8% reduction in future risk of stroke and coronary heart disease.^16,17

The Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease multicenter randomized clinical trial investigated the impact of treating obstructive sleep apnea with continuous positive airway pressure (CPAP) compared with usual care.¹⁸ Although no statistically significant difference was seen in the composite cardiovascular outcome, propensity-score analysis in the subgroup adherent to CPAP demonstrated a lower composite of cerebral events in those who used CPAP for at least 4 hours a day.

The findings from this trial are difficult to interpret for several reasons. Adherence to CPAP was suboptimal, the severity of obstructive sleep apnea might not have been bad enough to permit observation of a significant treatment effect, and the generalizability of the findings is unclear, given that many of the participants were from underresourced regions.¹⁹

In a meta-analysis of cohort studies comprising more than 3 million participants, Fu et al found that the cardiovascular mortality rate was 63% lower in those with obstructive sleep apnea using CPAP than in untreated patients.²⁰

APPLY CLINICAL JUDGMENT

Overall, the USPSTF report is intended to guide healthcare decision-makers. However, it includes a caveat to not substitute the findings for clinical judgment and to interpret the findings in the context of collateral pertinent information.²

Although no high-quality data exist to support or refute global screening for obstructive sleep apnea in the primary care setting, the high prevalence of this disease and its detrimental effects on health and quality of life if left untreated should not be dismissed.

Arguably, most patients who present to primary care clinics are not healthy, are not free of symptoms, and are at risk of obstructive sleep apnea because they are obese. Testing for it is therefore more like case-finding than screening.

In view of the serious consequences of obstructive sleep apnea, we should view the situation as an opportunity to examine the impact of screening. Perhaps using electronic medical records, we could collect sleep-specific measures, implement case-finding strategies, and perform pragmatic clinical trials to inform and guide optimal and cost-effective screening approaches.

Patients with common disorders such as obstructive sleep apnea are often considered asymptomatic until asked about symptoms. Therefore, careful review of systems incorporating sleep health is important, particularly as patients do not typically volunteer this information. Obtaining this history does not necessarily fall under the USPSTF’s recommendation not to screen.

Future efforts should focus on leveraging the electronic medical record platform to collect sleep-specific measures, implementing case-finding strategies, and performing pragmatic clinical trials in the primary care setting to inform and guide optimal and cost-effective approaches to screening.

A 54-year-old female smoker was admitted to the hospital for fever and respiratory infection. On the day of admission, she reported lesions of the oral mucosa for the past several months. She denied taking any medications recently.

Physical examination showed brownish papillary lesions spread across the dorsum of the tongue; the lesions were a darker shade proximally (Figure 1), leading to the diagnosis of black hairy tongue. Hygienic measures were recommended, with other treatment options to be considered later, if necessary. Of note, during her 1-week hospital stay, she was treated with levofloxacin for the respiratory infection, and she did not smoke during this period. One week after her admission, the lesions had disappeared (Figure 2).

LINGUA VILLOSA NIGRA

Black hairy tongue (lingua villosa nigra) is a rare but benign condition caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. Causes that have been proposed include medications, hyposalivation, poor oral hygiene, oxidizing mouthwashes (eg, hydrogen peroxide), alcohol, smoking, and infection.¹

The differential diagnosis includes acanthosis nigricans, oral hairy leukoplakia, oral candidiasis, pigmented fungiform papillae, Addison disease, and black staining over a normal tongue from bismuth or food colorings.

DIAGNOSIS AND TREATMENT

Visual inspection and a detailed history are often sufficient for diagnosis. The optimal treatment is unclear, but the condition can improve with hygienic measures alone, topical or oral retinoids,² topical triamcinolone acetonide, salicylic acid, vitamin B complex, or antifungals. There are isolated cases in the literature in which improvement occurred with antibiotics, but their role is unclear.¹ Rarely, surgical excision of the filliform papilla in black hairy tongue has been done for symptomatic relief and cosmetic purposes.³

While our patient presented with typical features of black hairy tongue, which resolved with hygienic measures and smoking cessation, we could not completely rule out the contribution of antibiotics given for the respiratory infection. It is important to keep this disease in mind to avoid unnecessary tests and to apply the most appropriate treatment according to the patient’s symptoms.

A 54-year-old female smoker was admitted to the hospital for fever and respiratory infection. On the day of admission, she reported lesions of the oral mucosa for the past several months. She denied taking any medications recently.

Physical examination showed brownish papillary lesions spread across the dorsum of the tongue; the lesions were a darker shade proximally (Figure 1), leading to the diagnosis of black hairy tongue. Hygienic measures were recommended, with other treatment options to be considered later, if necessary. Of note, during her 1-week hospital stay, she was treated with levofloxacin for the respiratory infection, and she did not smoke during this period. One week after her admission, the lesions had disappeared (Figure 2).

LINGUA VILLOSA NIGRA

Black hairy tongue (lingua villosa nigra) is a rare but benign condition caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. Causes that have been proposed include medications, hyposalivation, poor oral hygiene, oxidizing mouthwashes (eg, hydrogen peroxide), alcohol, smoking, and infection.¹

The differential diagnosis includes acanthosis nigricans, oral hairy leukoplakia, oral candidiasis, pigmented fungiform papillae, Addison disease, and black staining over a normal tongue from bismuth or food colorings.

DIAGNOSIS AND TREATMENT

Visual inspection and a detailed history are often sufficient for diagnosis. The optimal treatment is unclear, but the condition can improve with hygienic measures alone, topical or oral retinoids,² topical triamcinolone acetonide, salicylic acid, vitamin B complex, or antifungals. There are isolated cases in the literature in which improvement occurred with antibiotics, but their role is unclear.¹ Rarely, surgical excision of the filliform papilla in black hairy tongue has been done for symptomatic relief and cosmetic purposes.³

While our patient presented with typical features of black hairy tongue, which resolved with hygienic measures and smoking cessation, we could not completely rule out the contribution of antibiotics given for the respiratory infection. It is important to keep this disease in mind to avoid unnecessary tests and to apply the most appropriate treatment according to the patient’s symptoms.

A 54-year-old female smoker was admitted to the hospital for fever and respiratory infection. On the day of admission, she reported lesions of the oral mucosa for the past several months. She denied taking any medications recently.

Physical examination showed brownish papillary lesions spread across the dorsum of the tongue; the lesions were a darker shade proximally (Figure 1), leading to the diagnosis of black hairy tongue. Hygienic measures were recommended, with other treatment options to be considered later, if necessary. Of note, during her 1-week hospital stay, she was treated with levofloxacin for the respiratory infection, and she did not smoke during this period. One week after her admission, the lesions had disappeared (Figure 2).

LINGUA VILLOSA NIGRA

Black hairy tongue (lingua villosa nigra) is a rare but benign condition caused by defective desquamation and reactive hypertrophy of the filiform papillae of the tongue. Causes that have been proposed include medications, hyposalivation, poor oral hygiene, oxidizing mouthwashes (eg, hydrogen peroxide), alcohol, smoking, and infection.¹

The differential diagnosis includes acanthosis nigricans, oral hairy leukoplakia, oral candidiasis, pigmented fungiform papillae, Addison disease, and black staining over a normal tongue from bismuth or food colorings.

DIAGNOSIS AND TREATMENT

Visual inspection and a detailed history are often sufficient for diagnosis. The optimal treatment is unclear, but the condition can improve with hygienic measures alone, topical or oral retinoids,² topical triamcinolone acetonide, salicylic acid, vitamin B complex, or antifungals. There are isolated cases in the literature in which improvement occurred with antibiotics, but their role is unclear.¹ Rarely, surgical excision of the filliform papilla in black hairy tongue has been done for symptomatic relief and cosmetic purposes.³

While our patient presented with typical features of black hairy tongue, which resolved with hygienic measures and smoking cessation, we could not completely rule out the contribution of antibiotics given for the respiratory infection. It is important to keep this disease in mind to avoid unnecessary tests and to apply the most appropriate treatment according to the patient’s symptoms.

Estrogen receptor agonist-antagonists (ERAAs), previously called selective estrogen receptor modulators (SERMs), have extended the options for treating the various conditions that menopausal women suffer from. These drugs act differently on estrogen receptors in different tissues, stimulating receptors in some tissues but inhibiting them in others. This allows selective inhibition or stimulation of estrogen-like action in various target tissues.¹

This article highlights the use of ERAAs to treat menopausal vasomotor symptoms (eg, hot flashes, night sweats), genitourinary syndrome of menopause, osteoporosis, breast cancer (and the risk of breast cancer), and other health concerns unique to women at midlife.

SYMPTOMS OF MENOPAUSE: COMMON AND TROUBLESOME

Vasomotor symptoms such as hot flashes and night sweats are common during perimenopause—most women experience them. They are most frequent during the menopause transition but can persist for 10 years or more afterward.²

Genitourinary syndrome of menopause is also common and often worsens with years after menopause.³ It can lead to dyspareunia and vaginal dryness, which may in turn result in lower libido, vaginismus, and hypoactive sexual desire disorder, problems that often arise at the same time as vaginal dryness and atrophy.⁴

Osteopenia and osteoporosis. A drop in systemic estrogen leads to a decline in bone mineral density, increasing the risk of fractures.⁵

ESTROGEN-PROGESTIN TREATMENT: THE GOLD STANDARD, BUT NOT IDEAL

The current gold standard for treating moderate to severe hot flashes is estrogen, available in oral, transdermal, and vaginal formulations.⁶ Estrogen also has antiresorptive effects on bone and is approved for preventing osteoporosis. Systemic estrogen may also be prescribed for genitourinary syndrome of menopause if local vaginal treatment alone is insufficient.

If women who have an intact uterus receive estrogen, they should also receive a progestin to protect against endometrial hyperplasia and reduce the risk of endometrial cancer.

Despite its status as the gold standard, estrogen-progestin therapy presents challenges. In some women, progestins cause side effects such as breast tenderness, bloating, fatigue, and depression.⁷ Estrogen-progestin therapy often causes vaginal bleeding, which for some women is troublesome or distressing; bleeding may be the reason for repeated evaluations, can increase anxiety, and can lead to poor adherence with hormonal treatment. Women who carry a higher-than-normal risk of developing breast cancer or fear that taking hormones will lead to breast cancer may show  decreased adherence to therapy. Women who have estrogen receptor-positive breast cancer cannot take estrogen.

Individualized options are needed for women who have progestin-related side effects, unwanted vaginal bleeding, or a higher risk of breast cancer.

WELCOME THE ERAAs

An ideal treatment for menopause would relieve vasomotor symptoms and genitourinary syndrome of menopause and increase bone mineral density without causing breast tenderness, vaginal bleeding, or endometrial proliferation.

The “designer estrogens,” or ERAAs, have specific positive effects on the bone, heart, and brain with neutral or antagonist effects on estrogen receptors in other tissues such as the breasts and endometrium.⁸ While not entirely free of adverse effects, these agents have been developed with the aim of minimizing the most common ones related to estrogen and progestin.

Several ERAAs are currently approved by the US Food and Drug Administration (FDA)for various indications, each having a unique profile. Clomifene was the first agent of this class, and it is still used clinically to induce ovulation. This article highlights subsequently approved agents, ie, tamoxifen, raloxifene, ospemifene, and the combination of conjugated estrogens and bazedoxifene (Table 1).

All ERAAs increase the risk of venous thromboembolism, and therefore none of them should be used in women with known venous thromboembolism or at high risk of it.

After clomiphene, tamoxifen was the second ERAA on the market. Although researchers were looking for a new contraceptive drug, they found tamoxifen to be useful as a chemotherapeutic agent for breast cancer. First used in 1971, tamoxifen continues to be one of the most commonly prescribed chemotherapeutic medications today.

The FDA has approved tamoxifen to treat breast cancer as well as to prevent breast cancer in pre- and postmenopausal women at risk. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses for it.

Trials of tamoxifen for cancer treatment

The Early Breast Cancer Trialists’ Collaborative Group⁹ performed a meta-analysis and found that 5 years of adjuvant treatment with tamoxifen is associated with a 26% reduction in mortality and a 47% reduction in breast cancer recurrence at 10 years. In absolute terms, we estimate that 21 women would need to be treated to prevent 1 death and 8 would need to be treated to prevent 1 recurrence.

The ATLAS Trial (Adjuvant Tamoxifen Longer Against Shorter)¹⁰ and later the UK ATTOM (Adjuvant Tamoxifen Treatment to Offer More)¹¹ trial confirmed an even greater reduction in recurrence and mortality after a total of 10 years of treatment.

Trials of tamoxifen for cancer prevention

Cuzik et al¹² performed a meta-analysis of 4 trials of tamoxifen’s effectiveness in preventing breast cancer for women at elevated risk. The incidence of estrogen receptor-positive breast cancer was 48% lower with tamoxifen use, but there was no effect on estrogen-negative breast cancer. From their data, we estimate that 77 women would need to be treated to prevent 1 case of breast cancer.

The IBIS-I trial (International Breast Cancer Intervention Study I)¹³ found that, in healthy women at high risk of breast cancer, the benefit of taking tamoxifen for 5 years as preventive treatment persisted long afterward. The investigators estimated that at 20 years of follow-up the risk of breast cancer would be 12.3% in placebo recipients and 7.8% in tamoxifen recipients, a 4.5% absolute risk reduction; number needed to treat (NNT) 22.

Data on tamoxifen and osteoporosis

The Breast Cancer Prevention Trial revealed a 19% reduction in the incidence of osteoporotic fractures with tamoxifen, but the difference was not statistically significant.¹⁴ The 1-year rates of fracture in women age 50 and older were 0.727% with placebo and 0.567% with tamoxifen, an absolute difference of 0.151%; therefore, if the effect is real, 662 women age 50 or older would need to be treated for 1 year to prevent 1 fracture. Tamoxifen is not FDA-approved to treat osteoporosis.

Data on tamoxifen and cardiovascular risk reduction

Chang et al,¹⁵ in a study in women at risk of breast cancer, incidentally found that tamoxifen was associated with a 13% reduction in total cholesterol compared with placebo.

Herrington and Klein,¹⁶ in a systematic review, noted similar findings in multiple studies of tamoxifen, with decreases in total cholesterol ranging from 7% to 17% and decreases in low-density lipoprotein cholesterol ranging from 10% to 28%. However, they found no change in high-density lipoprotein cholesterol concentrations or in the cardiovascular mortality rate.

The ATLAS trial¹⁰ revealed a relative risk reduction of 0.76 (95% confidence interval [CI] 0.60–0.95, P = .02) in ischemic heart disease for women who took tamoxifen for 10 years compared with 5 years. We calculate that ischemic heart disease occurred in 163 (2.5%) of 6,440 women who took tamoxifen for 5 years compared with 127 (1.9%) of 6,454 women who took it for 10 years, a 0.6% absolute risk reduction, NNT = 167.

Adverse effects of tamoxifen

Uterine neoplasia. Women taking tamoxifen have a 2.5-fold increased risk of endometrial cancer.¹⁴ Tamoxifen also increases the risk of benign uterine disease such as endometrial hyperplasia and polyps. As many as 39% of women taking tamoxifen will have evidence of benign uterine changes on pathology.¹⁷ Other adverse effects:

Venous thromboembolism (the risk of pulmonary embolism is increased approximately threefold¹⁴)

Cataracts (there is a slight increase in cataract diagnosis in tamoxifen users)

Vasomotor symptoms, which limit the use of tamoxifen in many women.

Ideal candidate for tamoxifen

The ideal candidate for tamoxifen is a woman with breast cancer that is estrogen receptor-positive and who has a history of osteopenia or osteoporosis and no risk factors for venous thromboembolism.

Raloxifene, a second-generation ERAA, was first approved for preventing and treating osteoporosis and later for reducing the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.

Trials of raloxifene for osteoporosis

The MORE trial (Multiple Outcomes of Raloxifene)¹⁸ was a large multicenter randomized double-blind study. Raloxifene recipients showed a significant increase in bone mineral density in the lumbar spine and femoral neck at year 3 (P < .001) compared with those receiving placebo. Even after only 1 year of treatment, raloxifene significantly reduced the risk of new fractures, despite only modest gains in bone mineral density. After 3 years of treatment, new clinical vertebral fractures had occurred in 3.5% of the placebo group compared with 2.1% of the group receiving raloxifene 60 mg.¹⁹ Relative risk reductions were similar in women who had already had a clinical vertebral fracture at baseline, whose absolute risk is higher. However, no significant effect was seen on the incidence of hip or nonvertebral fractures.

The CORE trial (Continuing Outcomes Relevant to Raloxifene)²⁰ extended the treatment of the women enrolled in the MORE trial another 4 years and found that the benefit of raloxifene with regard to bone mineral density persisted with continued use.

Trials of raloxifene for breast cancer prevention

The MORE trial,²¹ in postmenopausal women with osteoporosis included breast cancer as a secondary end point, and raloxifene was shown to decrease the incidence of invasive breast cancer. At a median of 40 months, invasive breast cancer had arisen in 13 (0.25%) of the 5,129 women assigned to raloxifene and 27 (1.0%) of the 2,576 women assigned to placebo. The authors calculated that 126 women would need to be treated to prevent 1 case of breast cancer.

The CORE trial,²² as noted, extended the treatment of the women enrolled in the MORE trial another 4 years. The risk of any invasive breast cancer in postmenopausal women with osteoporosis was significantly reduced by 59% after 8 years, and the risk of estrogen receptor-positive invasive breast cancer was reduced by 66%.

There is evidence that raloxifene’s effect on breast cancer risk persists after discontinuation of use.²³

Does raloxifene reduce mortality?

Grady et al²⁴ studied the effect of raloxifene on all-cause mortality in a pooled analysis of mortality data from the MORE, CORE, and Raloxifene Use for the Heart (RUTH)²⁵ trials. In older postmenopausal women, the rate of all-cause mortality was 8.65% in those taking placebo compared with 7.88% in those taking raloxifene 60 mg daily—10% lower. The mechanism behind the lower mortality rate is unclear, and Grady et al recommend that the finding be interpreted with caution.

Trials of raloxifene for heart protection

The RUTH trial²⁵ was a 5.6-year study undertaken to study the effects of raloxifene on coronary outcomes and invasive breast cancer in postmenopausal women. Results were mixed. Active treatment:

• Did not significantly affect the risk of coronary artery disease compared with placebo
• Significantly decreased the risk of invasive breast cancer
• Significantly decreased the risk of clinical vertebral fractures
• Increased the risk of fatal stroke (59 vs 39 events, hazard ratio 1.49, 95% CI 1.00–2.24) and venous thromboembolism (103 vs 71 events, hazard ratio 1.44, 95% CI 1.06–1.95).

The STAR trial (Study of Tamoxifen and Raloxifene)^26,27 compared raloxifene and tamoxifen in postmenopausal women at increased risk of breast cancer. Women were randomized to receive either tamoxifen 20 mg or raloxifene 60 mg for 5 years. Results:

• No difference in the number of new cases of invasive breast cancer between the groups
• Fewer cases of noninvasive breast cancer in the tamoxifen group, but the difference was not statistically significant
• Fewer cases of uterine cancer in the raloxifene group, annual incidence rates 0.125% vs 0.199%, absolute risk reduction 0.74%, NNT 1,351, relative risk with raloxifene 0.62, 95% CI 0.30–0.50
• Fewer thromboembolic events with raloxifene
• Fewer cataracts with raloxifene.

Adverse effects of raloxifene

Raloxifene increases the risk of venous thromboembolism and stroke in women at high risk of coronary artery disease.¹⁹

Ideal candidates for raloxifene

Postmenopausal women with osteopenia or osteoporosis and a higher risk of breast cancer who have minimal to no vasomotor symptoms or genitourinary syndrome of menopause are good candidates for raloxifene. Raloxifene is also a good choice for women who have genitourinary syndrome of menopause treated with local vaginal estrogen. Raloxifene has no effect on vasomotor symptoms or genitourinary syndrome of menopause.

Although ospemifene does not have the steroid structure of estrogen, it acts as an estrogen agonist specifically in the vaginal mucosa and an antagonist in other tissues.²⁸ It has been shown on Papanicolaou smears to reduce the number of parabasal cells and increase the number of intermediate and superficial cells after 3 months of treatment.²⁹

Ospemifene 60 mg taken orally with food is approved by the FDA to treat genitourinary syndrome of menopause.

Why ospemifene is needed

First-line treatment options for genitourinary syndrome of menopause include over-the-counter lubricants. However, there is no evidence that these products reverse vaginal atrophy,³⁰ and many women report no relief of symptoms with them.

While various local estrogen preparations positively affect genitourinary syndrome of menopause, some of them can be messy, which can limit-long term adherence.

In one of the largest surveys on genitourinary syndrome of menopause (the REVIVE survey—the Real Women’s View of Treatment Options for Menopausal Vaginal Changes²⁹), 59% of women reported that their vaginal symptoms negatively affected sexual activity. The problem affects not only the patient but also her sexual partner.³¹ Another large study showed that 38% of women and 39% of male partners reported that it had a worse-than-expected impact on their intimate relationships.³¹

Genitourinary syndrome of menopause also makes pelvic examinations difficult, may worsen or exacerbate cystitis, and may increase urinary tract infections.

Trials of ospemifene for genitourinary syndrome of menopause

To date, 3 randomized, double-blind clinical trials have demonstrated ospemifene 60 mg to be superior to placebo in treating genitourinary syndrome of menopause. Two were short-term (12-week) and showed significant positive changes in the percent of superficial cells, vaginal pH (lower is better), and number of parabasal cells, along with improvements in the Likert rating of both vaginal dryness and dyspareunia.^32,33

A long-term (52-week) randomized placebo-controlled trial compared ospemifene and placebo and showed significant improvement in vaginal maturation index and pH at weeks 12 and 52.³⁴ Other outcome measures included petechiae, pallor, friability, erythema, and dryness, all of which improved from baseline (P < .001). At the end of the trial, 80% of the patients who received ospemifene had no vaginal atrophy.

No serious adverse events were noted in any of the clinical trials to date, and a systemic review and meta-analysis demonstrated ospemifene to be safe and efficacious.³⁵ The most frequently reported reasons for discontinuation were hot flashes, vaginal discharge, muscle spasms, and hyperhidrosis, but the rates of these effects were similar to those with placebo.

Trial of ospemifene’s effect on bone turnover

As an estrogen receptor agonist in bone, ospemifene decreases the levels of bone turnover markers in postmenopausal women.³⁶ A study found ospemifene to be about as effective as raloxifene in suppressing bone turnover,³⁷ but ospemifene does not carry FDA approval for preventing or treating osteoporosis.

Other effects

In experiments in rats, the incidence of breast cancer appears to be lower with ospemifene, and the higher the dose, the lower the incidence.³⁸

Ospemifene also has antagonistic effects on uterine tissue, and no cases of endometrial hyperplasia or carcinoma have been reported in short-term or long-term studies.³⁵

Ospemifene has no effect however on vasomotor symptoms and may in fact worsen vasomotor symptoms in women suffering with hot flashes and night sweats. Further investigation into its long-term safety and effects on breast tissue and bone would provide more insight.

Ideal candidates for ospemifene

Ospemifene could help postmenopausal women with genitourinary syndrome of menopause for whom over-the-counter lubricants fail, who dislike local vaginal estrogen, or who decline systemic hormone therapy, and who do not meet the criteria for treatment with systemic hormone therapy.

CONJUGATED ESTROGENS AND BAZEDOXIFENE COMBINATION

A combination agent consisting of conjugated estrogens 0.45 mg plus bazedoxifene 20 mg has been approved by the FDA for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women who have an intact uterus.

Trials of estrogen-bazedoxifene for vasomotor symptoms

The Selective Estrogen Menopause and Response to Therapy (SMART) trials^39,40 were a series of randomized, double-blind, placebo-controlled phase 3 studies evaluating the efficacy and safety of the estrogen-bazedoxifene combination in postmenopausal women.

The SMART-2 trial³⁹ evaluated the combination of conjugated estrogens (either 0.45 mg or 0.625) plus bazedoxifene 20 mg and found both dosages significantly reduced the number and severity of hot flashes at weeks 4 and 12 (P < .001). At week 12, the combination with 0.45 mg of estrogen reduced vasomotor symptoms from baseline by 74% (10.3 hot flashes per week at baseline vs 2.8 at week 12); the combination with 0.625 mg of estrogen reduced vasomotor symptoms by 80% (10.4 vs 2.4 flashes); and placebo reduced them by 51% (10.5 vs 5.4 flashes).

For bone density. The SMART-1 trial⁴⁰ showed that the estrogen-bazedoxifene combination in both estrogen dosages significantly increased mean lumbar spine bone mineral density (P < .001) and total hip bone mineral density (P < .05) from baseline at 12 and 24 months compared with placebo. Increases in density tended to be higher with the higher estrogen dose (0.625 mg), but less with higher doses of bazedoxifene.⁴¹ At 24 months, the increase in bone mineral density was even greater than in women treated with raloxifene.⁴² However, the effect of estrogen-bazedoxifene on the incidence of fractures remains to be studied.

For genitourinary syndrome of menopause. The SMART-3 trial showed that treatment with conjugated estrogens plus bazedoxifene (0.45/20 mg or 0.625/20 mg) was more effective than placebo in increasing the percent of superficial and intermediate cells and decreased the number of parabasal cells at 12 weeks compared with placebo (P < .01).⁴³ Both doses also significantly decreased the mean vaginal pH and improved vaginal dryness.

Patients treated with estrogen-bazedoxifene for a minimum of 12 weeks in a double-blind placebo-controlled study also showed a significant improvement in sexual function and quality-of-life measurements based on 3 well-defined scales, which included ease of lubrication, satisfaction with treatment, control of hot flashes, and sleep parameters.⁴³

Low rates of side effects

To evaluate this regimen’s antagonistic effects on uterine tissue, endometrial hyperplasia was diagnosed by blinded pathologists using endometrial biopsies taken at 6, 12, and 24 months or more if cancer was a suspected diagnosis. At 12 and 24 months of treatment, the incidence of hyperplasia with bazedoxifene 20 or 40 mg at doses of either 0.45 or 0.625 mg of conjugated estrogens was less than 1%, which was similar to placebo rates over the 24 months.⁴⁴ The lowest dose studied, bazedoxifene 10 mg, did not prevent hyperplasia with conjugated estrogens 0.45 or 0.625 mg, and its use was discontinued.

Rates of amenorrhea with bazedoxifene 20 or 40 mg and conjugated estrogens 0.45 or 0.625 mg were very favorable (83%–93%) and similar to those with placebo.⁴⁵ For women with continued bleeding on hormone therapy requiring multiple evaluations, or for women who won’t accept the risk of bleeding on hormone therapy, conjugated estrogens and bazedoxifene may be a sustainable option. However, any woman with abnormal bleeding should undergo prompt immediate evaluation.

A typical side effect of estrogen replacement therapy is breast tenderness. For women seeking vasomotor symptom treatment but who experience breast tenderness, this may be a deterrent from continuing hormone therapy. As shown in the SMART-1 and SMART-2 trials,⁴⁶ conjugated estrogens and bazedoxifene did not cause an increase in breast tenderness, which may enhance medication adherence.

Ideal candidates for conjugated estrogens plus bazedoxifene

This product could help postmenopausal women who have an intact uterus and are suffering with moderate to severe vasomotor symptoms and genitourinary syndrome of menopause who cannot tolerate the side effects of hormone therapy such as bleeding, bloating, or breast tenderness, or who prefer to take an estrogen but without a progestin. It is also ideal for women at higher risk of osteoporosis.

WHO SHOULD GET WHAT?

Not all postmenopausal women have vasomotor symptoms, genitourinary syndrome of menopause, or bone loss. For those who do, standard hormone therapy is an option.

For those who have symptoms and a lower threshold of side effects such as breast tenderness and vaginal bleeding, a combination of an estrogen plus an ERAA (eg, bazedoxifene) is an option.

For women who have no vasomotor symptoms but do have genitourinary syndrome of menopause and don’t want local vaginal treatment, ospemifene is an option.

For women with no vasomotor symptoms but who have bone loss and increased risk of estrogen receptor-positive breast cancer, raloxifene is a good option.

Both premenopausal and postmenopausal women who are at increased risk for breast cancer should be considered for tamoxifen chemoprevention. Postmenopausal women with a uterus at increased risk for breast cancer should be considered for raloxifene, as it has no uterine effect. Raloxifene is not indicated in premenopausal women.

No woman at increased risk of venous thromboembolism is a candidate for ERAA treatment or for oral estrogen. However, the clinician has multiple options to improve quality of life and work productivity and reduce office visits of women at midlife, especially when they are individually assessed and treated.

Estrogen receptor agonist-antagonists (ERAAs), previously called selective estrogen receptor modulators (SERMs), have extended the options for treating the various conditions that menopausal women suffer from. These drugs act differently on estrogen receptors in different tissues, stimulating receptors in some tissues but inhibiting them in others. This allows selective inhibition or stimulation of estrogen-like action in various target tissues.¹

This article highlights the use of ERAAs to treat menopausal vasomotor symptoms (eg, hot flashes, night sweats), genitourinary syndrome of menopause, osteoporosis, breast cancer (and the risk of breast cancer), and other health concerns unique to women at midlife.

SYMPTOMS OF MENOPAUSE: COMMON AND TROUBLESOME

Vasomotor symptoms such as hot flashes and night sweats are common during perimenopause—most women experience them. They are most frequent during the menopause transition but can persist for 10 years or more afterward.²

Genitourinary syndrome of menopause is also common and often worsens with years after menopause.³ It can lead to dyspareunia and vaginal dryness, which may in turn result in lower libido, vaginismus, and hypoactive sexual desire disorder, problems that often arise at the same time as vaginal dryness and atrophy.⁴

Osteopenia and osteoporosis. A drop in systemic estrogen leads to a decline in bone mineral density, increasing the risk of fractures.⁵

ESTROGEN-PROGESTIN TREATMENT: THE GOLD STANDARD, BUT NOT IDEAL

The current gold standard for treating moderate to severe hot flashes is estrogen, available in oral, transdermal, and vaginal formulations.⁶ Estrogen also has antiresorptive effects on bone and is approved for preventing osteoporosis. Systemic estrogen may also be prescribed for genitourinary syndrome of menopause if local vaginal treatment alone is insufficient.

If women who have an intact uterus receive estrogen, they should also receive a progestin to protect against endometrial hyperplasia and reduce the risk of endometrial cancer.

Despite its status as the gold standard, estrogen-progestin therapy presents challenges. In some women, progestins cause side effects such as breast tenderness, bloating, fatigue, and depression.⁷ Estrogen-progestin therapy often causes vaginal bleeding, which for some women is troublesome or distressing; bleeding may be the reason for repeated evaluations, can increase anxiety, and can lead to poor adherence with hormonal treatment. Women who carry a higher-than-normal risk of developing breast cancer or fear that taking hormones will lead to breast cancer may show  decreased adherence to therapy. Women who have estrogen receptor-positive breast cancer cannot take estrogen.

Individualized options are needed for women who have progestin-related side effects, unwanted vaginal bleeding, or a higher risk of breast cancer.

WELCOME THE ERAAs

An ideal treatment for menopause would relieve vasomotor symptoms and genitourinary syndrome of menopause and increase bone mineral density without causing breast tenderness, vaginal bleeding, or endometrial proliferation.

The “designer estrogens,” or ERAAs, have specific positive effects on the bone, heart, and brain with neutral or antagonist effects on estrogen receptors in other tissues such as the breasts and endometrium.⁸ While not entirely free of adverse effects, these agents have been developed with the aim of minimizing the most common ones related to estrogen and progestin.

Several ERAAs are currently approved by the US Food and Drug Administration (FDA)for various indications, each having a unique profile. Clomifene was the first agent of this class, and it is still used clinically to induce ovulation. This article highlights subsequently approved agents, ie, tamoxifen, raloxifene, ospemifene, and the combination of conjugated estrogens and bazedoxifene (Table 1).

All ERAAs increase the risk of venous thromboembolism, and therefore none of them should be used in women with known venous thromboembolism or at high risk of it.

After clomiphene, tamoxifen was the second ERAA on the market. Although researchers were looking for a new contraceptive drug, they found tamoxifen to be useful as a chemotherapeutic agent for breast cancer. First used in 1971, tamoxifen continues to be one of the most commonly prescribed chemotherapeutic medications today.

The FDA has approved tamoxifen to treat breast cancer as well as to prevent breast cancer in pre- and postmenopausal women at risk. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses for it.

Trials of tamoxifen for cancer treatment

The Early Breast Cancer Trialists’ Collaborative Group⁹ performed a meta-analysis and found that 5 years of adjuvant treatment with tamoxifen is associated with a 26% reduction in mortality and a 47% reduction in breast cancer recurrence at 10 years. In absolute terms, we estimate that 21 women would need to be treated to prevent 1 death and 8 would need to be treated to prevent 1 recurrence.

The ATLAS Trial (Adjuvant Tamoxifen Longer Against Shorter)¹⁰ and later the UK ATTOM (Adjuvant Tamoxifen Treatment to Offer More)¹¹ trial confirmed an even greater reduction in recurrence and mortality after a total of 10 years of treatment.

Trials of tamoxifen for cancer prevention

Cuzik et al¹² performed a meta-analysis of 4 trials of tamoxifen’s effectiveness in preventing breast cancer for women at elevated risk. The incidence of estrogen receptor-positive breast cancer was 48% lower with tamoxifen use, but there was no effect on estrogen-negative breast cancer. From their data, we estimate that 77 women would need to be treated to prevent 1 case of breast cancer.

The IBIS-I trial (International Breast Cancer Intervention Study I)¹³ found that, in healthy women at high risk of breast cancer, the benefit of taking tamoxifen for 5 years as preventive treatment persisted long afterward. The investigators estimated that at 20 years of follow-up the risk of breast cancer would be 12.3% in placebo recipients and 7.8% in tamoxifen recipients, a 4.5% absolute risk reduction; number needed to treat (NNT) 22.

Data on tamoxifen and osteoporosis

The Breast Cancer Prevention Trial revealed a 19% reduction in the incidence of osteoporotic fractures with tamoxifen, but the difference was not statistically significant.¹⁴ The 1-year rates of fracture in women age 50 and older were 0.727% with placebo and 0.567% with tamoxifen, an absolute difference of 0.151%; therefore, if the effect is real, 662 women age 50 or older would need to be treated for 1 year to prevent 1 fracture. Tamoxifen is not FDA-approved to treat osteoporosis.

Data on tamoxifen and cardiovascular risk reduction

Chang et al,¹⁵ in a study in women at risk of breast cancer, incidentally found that tamoxifen was associated with a 13% reduction in total cholesterol compared with placebo.

Herrington and Klein,¹⁶ in a systematic review, noted similar findings in multiple studies of tamoxifen, with decreases in total cholesterol ranging from 7% to 17% and decreases in low-density lipoprotein cholesterol ranging from 10% to 28%. However, they found no change in high-density lipoprotein cholesterol concentrations or in the cardiovascular mortality rate.

The ATLAS trial¹⁰ revealed a relative risk reduction of 0.76 (95% confidence interval [CI] 0.60–0.95, P = .02) in ischemic heart disease for women who took tamoxifen for 10 years compared with 5 years. We calculate that ischemic heart disease occurred in 163 (2.5%) of 6,440 women who took tamoxifen for 5 years compared with 127 (1.9%) of 6,454 women who took it for 10 years, a 0.6% absolute risk reduction, NNT = 167.

Adverse effects of tamoxifen

Uterine neoplasia. Women taking tamoxifen have a 2.5-fold increased risk of endometrial cancer.¹⁴ Tamoxifen also increases the risk of benign uterine disease such as endometrial hyperplasia and polyps. As many as 39% of women taking tamoxifen will have evidence of benign uterine changes on pathology.¹⁷ Other adverse effects:

Venous thromboembolism (the risk of pulmonary embolism is increased approximately threefold¹⁴)

Cataracts (there is a slight increase in cataract diagnosis in tamoxifen users)

Vasomotor symptoms, which limit the use of tamoxifen in many women.

Ideal candidate for tamoxifen

The ideal candidate for tamoxifen is a woman with breast cancer that is estrogen receptor-positive and who has a history of osteopenia or osteoporosis and no risk factors for venous thromboembolism.

Raloxifene, a second-generation ERAA, was first approved for preventing and treating osteoporosis and later for reducing the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.

Trials of raloxifene for osteoporosis

The MORE trial (Multiple Outcomes of Raloxifene)¹⁸ was a large multicenter randomized double-blind study. Raloxifene recipients showed a significant increase in bone mineral density in the lumbar spine and femoral neck at year 3 (P < .001) compared with those receiving placebo. Even after only 1 year of treatment, raloxifene significantly reduced the risk of new fractures, despite only modest gains in bone mineral density. After 3 years of treatment, new clinical vertebral fractures had occurred in 3.5% of the placebo group compared with 2.1% of the group receiving raloxifene 60 mg.¹⁹ Relative risk reductions were similar in women who had already had a clinical vertebral fracture at baseline, whose absolute risk is higher. However, no significant effect was seen on the incidence of hip or nonvertebral fractures.

The CORE trial (Continuing Outcomes Relevant to Raloxifene)²⁰ extended the treatment of the women enrolled in the MORE trial another 4 years and found that the benefit of raloxifene with regard to bone mineral density persisted with continued use.

Trials of raloxifene for breast cancer prevention

The MORE trial,²¹ in postmenopausal women with osteoporosis included breast cancer as a secondary end point, and raloxifene was shown to decrease the incidence of invasive breast cancer. At a median of 40 months, invasive breast cancer had arisen in 13 (0.25%) of the 5,129 women assigned to raloxifene and 27 (1.0%) of the 2,576 women assigned to placebo. The authors calculated that 126 women would need to be treated to prevent 1 case of breast cancer.

The CORE trial,²² as noted, extended the treatment of the women enrolled in the MORE trial another 4 years. The risk of any invasive breast cancer in postmenopausal women with osteoporosis was significantly reduced by 59% after 8 years, and the risk of estrogen receptor-positive invasive breast cancer was reduced by 66%.

There is evidence that raloxifene’s effect on breast cancer risk persists after discontinuation of use.²³

Does raloxifene reduce mortality?

Grady et al²⁴ studied the effect of raloxifene on all-cause mortality in a pooled analysis of mortality data from the MORE, CORE, and Raloxifene Use for the Heart (RUTH)²⁵ trials. In older postmenopausal women, the rate of all-cause mortality was 8.65% in those taking placebo compared with 7.88% in those taking raloxifene 60 mg daily—10% lower. The mechanism behind the lower mortality rate is unclear, and Grady et al recommend that the finding be interpreted with caution.

Trials of raloxifene for heart protection

The RUTH trial²⁵ was a 5.6-year study undertaken to study the effects of raloxifene on coronary outcomes and invasive breast cancer in postmenopausal women. Results were mixed. Active treatment:

• Did not significantly affect the risk of coronary artery disease compared with placebo
• Significantly decreased the risk of invasive breast cancer
• Significantly decreased the risk of clinical vertebral fractures
• Increased the risk of fatal stroke (59 vs 39 events, hazard ratio 1.49, 95% CI 1.00–2.24) and venous thromboembolism (103 vs 71 events, hazard ratio 1.44, 95% CI 1.06–1.95).

The STAR trial (Study of Tamoxifen and Raloxifene)^26,27 compared raloxifene and tamoxifen in postmenopausal women at increased risk of breast cancer. Women were randomized to receive either tamoxifen 20 mg or raloxifene 60 mg for 5 years. Results:

• No difference in the number of new cases of invasive breast cancer between the groups
• Fewer cases of noninvasive breast cancer in the tamoxifen group, but the difference was not statistically significant
• Fewer cases of uterine cancer in the raloxifene group, annual incidence rates 0.125% vs 0.199%, absolute risk reduction 0.74%, NNT 1,351, relative risk with raloxifene 0.62, 95% CI 0.30–0.50
• Fewer thromboembolic events with raloxifene
• Fewer cataracts with raloxifene.

Adverse effects of raloxifene

Raloxifene increases the risk of venous thromboembolism and stroke in women at high risk of coronary artery disease.¹⁹

Ideal candidates for raloxifene

Postmenopausal women with osteopenia or osteoporosis and a higher risk of breast cancer who have minimal to no vasomotor symptoms or genitourinary syndrome of menopause are good candidates for raloxifene. Raloxifene is also a good choice for women who have genitourinary syndrome of menopause treated with local vaginal estrogen. Raloxifene has no effect on vasomotor symptoms or genitourinary syndrome of menopause.

Although ospemifene does not have the steroid structure of estrogen, it acts as an estrogen agonist specifically in the vaginal mucosa and an antagonist in other tissues.²⁸ It has been shown on Papanicolaou smears to reduce the number of parabasal cells and increase the number of intermediate and superficial cells after 3 months of treatment.²⁹

Ospemifene 60 mg taken orally with food is approved by the FDA to treat genitourinary syndrome of menopause.

Why ospemifene is needed

First-line treatment options for genitourinary syndrome of menopause include over-the-counter lubricants. However, there is no evidence that these products reverse vaginal atrophy,³⁰ and many women report no relief of symptoms with them.

While various local estrogen preparations positively affect genitourinary syndrome of menopause, some of them can be messy, which can limit-long term adherence.

In one of the largest surveys on genitourinary syndrome of menopause (the REVIVE survey—the Real Women’s View of Treatment Options for Menopausal Vaginal Changes²⁹), 59% of women reported that their vaginal symptoms negatively affected sexual activity. The problem affects not only the patient but also her sexual partner.³¹ Another large study showed that 38% of women and 39% of male partners reported that it had a worse-than-expected impact on their intimate relationships.³¹

Genitourinary syndrome of menopause also makes pelvic examinations difficult, may worsen or exacerbate cystitis, and may increase urinary tract infections.

Trials of ospemifene for genitourinary syndrome of menopause

To date, 3 randomized, double-blind clinical trials have demonstrated ospemifene 60 mg to be superior to placebo in treating genitourinary syndrome of menopause. Two were short-term (12-week) and showed significant positive changes in the percent of superficial cells, vaginal pH (lower is better), and number of parabasal cells, along with improvements in the Likert rating of both vaginal dryness and dyspareunia.^32,33

A long-term (52-week) randomized placebo-controlled trial compared ospemifene and placebo and showed significant improvement in vaginal maturation index and pH at weeks 12 and 52.³⁴ Other outcome measures included petechiae, pallor, friability, erythema, and dryness, all of which improved from baseline (P < .001). At the end of the trial, 80% of the patients who received ospemifene had no vaginal atrophy.

No serious adverse events were noted in any of the clinical trials to date, and a systemic review and meta-analysis demonstrated ospemifene to be safe and efficacious.³⁵ The most frequently reported reasons for discontinuation were hot flashes, vaginal discharge, muscle spasms, and hyperhidrosis, but the rates of these effects were similar to those with placebo.

Trial of ospemifene’s effect on bone turnover

As an estrogen receptor agonist in bone, ospemifene decreases the levels of bone turnover markers in postmenopausal women.³⁶ A study found ospemifene to be about as effective as raloxifene in suppressing bone turnover,³⁷ but ospemifene does not carry FDA approval for preventing or treating osteoporosis.

Other effects

In experiments in rats, the incidence of breast cancer appears to be lower with ospemifene, and the higher the dose, the lower the incidence.³⁸

Ospemifene also has antagonistic effects on uterine tissue, and no cases of endometrial hyperplasia or carcinoma have been reported in short-term or long-term studies.³⁵

Ospemifene has no effect however on vasomotor symptoms and may in fact worsen vasomotor symptoms in women suffering with hot flashes and night sweats. Further investigation into its long-term safety and effects on breast tissue and bone would provide more insight.

Ideal candidates for ospemifene

Ospemifene could help postmenopausal women with genitourinary syndrome of menopause for whom over-the-counter lubricants fail, who dislike local vaginal estrogen, or who decline systemic hormone therapy, and who do not meet the criteria for treatment with systemic hormone therapy.

CONJUGATED ESTROGENS AND BAZEDOXIFENE COMBINATION

A combination agent consisting of conjugated estrogens 0.45 mg plus bazedoxifene 20 mg has been approved by the FDA for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women who have an intact uterus.

Trials of estrogen-bazedoxifene for vasomotor symptoms

The Selective Estrogen Menopause and Response to Therapy (SMART) trials^39,40 were a series of randomized, double-blind, placebo-controlled phase 3 studies evaluating the efficacy and safety of the estrogen-bazedoxifene combination in postmenopausal women.

The SMART-2 trial³⁹ evaluated the combination of conjugated estrogens (either 0.45 mg or 0.625) plus bazedoxifene 20 mg and found both dosages significantly reduced the number and severity of hot flashes at weeks 4 and 12 (P < .001). At week 12, the combination with 0.45 mg of estrogen reduced vasomotor symptoms from baseline by 74% (10.3 hot flashes per week at baseline vs 2.8 at week 12); the combination with 0.625 mg of estrogen reduced vasomotor symptoms by 80% (10.4 vs 2.4 flashes); and placebo reduced them by 51% (10.5 vs 5.4 flashes).

For bone density. The SMART-1 trial⁴⁰ showed that the estrogen-bazedoxifene combination in both estrogen dosages significantly increased mean lumbar spine bone mineral density (P < .001) and total hip bone mineral density (P < .05) from baseline at 12 and 24 months compared with placebo. Increases in density tended to be higher with the higher estrogen dose (0.625 mg), but less with higher doses of bazedoxifene.⁴¹ At 24 months, the increase in bone mineral density was even greater than in women treated with raloxifene.⁴² However, the effect of estrogen-bazedoxifene on the incidence of fractures remains to be studied.

For genitourinary syndrome of menopause. The SMART-3 trial showed that treatment with conjugated estrogens plus bazedoxifene (0.45/20 mg or 0.625/20 mg) was more effective than placebo in increasing the percent of superficial and intermediate cells and decreased the number of parabasal cells at 12 weeks compared with placebo (P < .01).⁴³ Both doses also significantly decreased the mean vaginal pH and improved vaginal dryness.

Patients treated with estrogen-bazedoxifene for a minimum of 12 weeks in a double-blind placebo-controlled study also showed a significant improvement in sexual function and quality-of-life measurements based on 3 well-defined scales, which included ease of lubrication, satisfaction with treatment, control of hot flashes, and sleep parameters.⁴³

Low rates of side effects

To evaluate this regimen’s antagonistic effects on uterine tissue, endometrial hyperplasia was diagnosed by blinded pathologists using endometrial biopsies taken at 6, 12, and 24 months or more if cancer was a suspected diagnosis. At 12 and 24 months of treatment, the incidence of hyperplasia with bazedoxifene 20 or 40 mg at doses of either 0.45 or 0.625 mg of conjugated estrogens was less than 1%, which was similar to placebo rates over the 24 months.⁴⁴ The lowest dose studied, bazedoxifene 10 mg, did not prevent hyperplasia with conjugated estrogens 0.45 or 0.625 mg, and its use was discontinued.

Rates of amenorrhea with bazedoxifene 20 or 40 mg and conjugated estrogens 0.45 or 0.625 mg were very favorable (83%–93%) and similar to those with placebo.⁴⁵ For women with continued bleeding on hormone therapy requiring multiple evaluations, or for women who won’t accept the risk of bleeding on hormone therapy, conjugated estrogens and bazedoxifene may be a sustainable option. However, any woman with abnormal bleeding should undergo prompt immediate evaluation.

A typical side effect of estrogen replacement therapy is breast tenderness. For women seeking vasomotor symptom treatment but who experience breast tenderness, this may be a deterrent from continuing hormone therapy. As shown in the SMART-1 and SMART-2 trials,⁴⁶ conjugated estrogens and bazedoxifene did not cause an increase in breast tenderness, which may enhance medication adherence.

Ideal candidates for conjugated estrogens plus bazedoxifene

This product could help postmenopausal women who have an intact uterus and are suffering with moderate to severe vasomotor symptoms and genitourinary syndrome of menopause who cannot tolerate the side effects of hormone therapy such as bleeding, bloating, or breast tenderness, or who prefer to take an estrogen but without a progestin. It is also ideal for women at higher risk of osteoporosis.

WHO SHOULD GET WHAT?

Not all postmenopausal women have vasomotor symptoms, genitourinary syndrome of menopause, or bone loss. For those who do, standard hormone therapy is an option.

For those who have symptoms and a lower threshold of side effects such as breast tenderness and vaginal bleeding, a combination of an estrogen plus an ERAA (eg, bazedoxifene) is an option.

For women who have no vasomotor symptoms but do have genitourinary syndrome of menopause and don’t want local vaginal treatment, ospemifene is an option.

For women with no vasomotor symptoms but who have bone loss and increased risk of estrogen receptor-positive breast cancer, raloxifene is a good option.

Both premenopausal and postmenopausal women who are at increased risk for breast cancer should be considered for tamoxifen chemoprevention. Postmenopausal women with a uterus at increased risk for breast cancer should be considered for raloxifene, as it has no uterine effect. Raloxifene is not indicated in premenopausal women.

No woman at increased risk of venous thromboembolism is a candidate for ERAA treatment or for oral estrogen. However, the clinician has multiple options to improve quality of life and work productivity and reduce office visits of women at midlife, especially when they are individually assessed and treated.

Estrogen receptor agonist-antagonists (ERAAs), previously called selective estrogen receptor modulators (SERMs), have extended the options for treating the various conditions that menopausal women suffer from. These drugs act differently on estrogen receptors in different tissues, stimulating receptors in some tissues but inhibiting them in others. This allows selective inhibition or stimulation of estrogen-like action in various target tissues.¹

This article highlights the use of ERAAs to treat menopausal vasomotor symptoms (eg, hot flashes, night sweats), genitourinary syndrome of menopause, osteoporosis, breast cancer (and the risk of breast cancer), and other health concerns unique to women at midlife.

SYMPTOMS OF MENOPAUSE: COMMON AND TROUBLESOME

Vasomotor symptoms such as hot flashes and night sweats are common during perimenopause—most women experience them. They are most frequent during the menopause transition but can persist for 10 years or more afterward.²

Genitourinary syndrome of menopause is also common and often worsens with years after menopause.³ It can lead to dyspareunia and vaginal dryness, which may in turn result in lower libido, vaginismus, and hypoactive sexual desire disorder, problems that often arise at the same time as vaginal dryness and atrophy.⁴

Osteopenia and osteoporosis. A drop in systemic estrogen leads to a decline in bone mineral density, increasing the risk of fractures.⁵

ESTROGEN-PROGESTIN TREATMENT: THE GOLD STANDARD, BUT NOT IDEAL

The current gold standard for treating moderate to severe hot flashes is estrogen, available in oral, transdermal, and vaginal formulations.⁶ Estrogen also has antiresorptive effects on bone and is approved for preventing osteoporosis. Systemic estrogen may also be prescribed for genitourinary syndrome of menopause if local vaginal treatment alone is insufficient.

If women who have an intact uterus receive estrogen, they should also receive a progestin to protect against endometrial hyperplasia and reduce the risk of endometrial cancer.

Despite its status as the gold standard, estrogen-progestin therapy presents challenges. In some women, progestins cause side effects such as breast tenderness, bloating, fatigue, and depression.⁷ Estrogen-progestin therapy often causes vaginal bleeding, which for some women is troublesome or distressing; bleeding may be the reason for repeated evaluations, can increase anxiety, and can lead to poor adherence with hormonal treatment. Women who carry a higher-than-normal risk of developing breast cancer or fear that taking hormones will lead to breast cancer may show  decreased adherence to therapy. Women who have estrogen receptor-positive breast cancer cannot take estrogen.

Individualized options are needed for women who have progestin-related side effects, unwanted vaginal bleeding, or a higher risk of breast cancer.

WELCOME THE ERAAs

An ideal treatment for menopause would relieve vasomotor symptoms and genitourinary syndrome of menopause and increase bone mineral density without causing breast tenderness, vaginal bleeding, or endometrial proliferation.

The “designer estrogens,” or ERAAs, have specific positive effects on the bone, heart, and brain with neutral or antagonist effects on estrogen receptors in other tissues such as the breasts and endometrium.⁸ While not entirely free of adverse effects, these agents have been developed with the aim of minimizing the most common ones related to estrogen and progestin.

Several ERAAs are currently approved by the US Food and Drug Administration (FDA)for various indications, each having a unique profile. Clomifene was the first agent of this class, and it is still used clinically to induce ovulation. This article highlights subsequently approved agents, ie, tamoxifen, raloxifene, ospemifene, and the combination of conjugated estrogens and bazedoxifene (Table 1).

All ERAAs increase the risk of venous thromboembolism, and therefore none of them should be used in women with known venous thromboembolism or at high risk of it.

After clomiphene, tamoxifen was the second ERAA on the market. Although researchers were looking for a new contraceptive drug, they found tamoxifen to be useful as a chemotherapeutic agent for breast cancer. First used in 1971, tamoxifen continues to be one of the most commonly prescribed chemotherapeutic medications today.

The FDA has approved tamoxifen to treat breast cancer as well as to prevent breast cancer in pre- and postmenopausal women at risk. It may also have beneficial effects on bone and on cardiovascular risk factors, but these are not approved uses for it.

Trials of tamoxifen for cancer treatment

The Early Breast Cancer Trialists’ Collaborative Group⁹ performed a meta-analysis and found that 5 years of adjuvant treatment with tamoxifen is associated with a 26% reduction in mortality and a 47% reduction in breast cancer recurrence at 10 years. In absolute terms, we estimate that 21 women would need to be treated to prevent 1 death and 8 would need to be treated to prevent 1 recurrence.

The ATLAS Trial (Adjuvant Tamoxifen Longer Against Shorter)¹⁰ and later the UK ATTOM (Adjuvant Tamoxifen Treatment to Offer More)¹¹ trial confirmed an even greater reduction in recurrence and mortality after a total of 10 years of treatment.

Trials of tamoxifen for cancer prevention

Cuzik et al¹² performed a meta-analysis of 4 trials of tamoxifen’s effectiveness in preventing breast cancer for women at elevated risk. The incidence of estrogen receptor-positive breast cancer was 48% lower with tamoxifen use, but there was no effect on estrogen-negative breast cancer. From their data, we estimate that 77 women would need to be treated to prevent 1 case of breast cancer.

The IBIS-I trial (International Breast Cancer Intervention Study I)¹³ found that, in healthy women at high risk of breast cancer, the benefit of taking tamoxifen for 5 years as preventive treatment persisted long afterward. The investigators estimated that at 20 years of follow-up the risk of breast cancer would be 12.3% in placebo recipients and 7.8% in tamoxifen recipients, a 4.5% absolute risk reduction; number needed to treat (NNT) 22.

Data on tamoxifen and osteoporosis

The Breast Cancer Prevention Trial revealed a 19% reduction in the incidence of osteoporotic fractures with tamoxifen, but the difference was not statistically significant.¹⁴ The 1-year rates of fracture in women age 50 and older were 0.727% with placebo and 0.567% with tamoxifen, an absolute difference of 0.151%; therefore, if the effect is real, 662 women age 50 or older would need to be treated for 1 year to prevent 1 fracture. Tamoxifen is not FDA-approved to treat osteoporosis.

Data on tamoxifen and cardiovascular risk reduction

Chang et al,¹⁵ in a study in women at risk of breast cancer, incidentally found that tamoxifen was associated with a 13% reduction in total cholesterol compared with placebo.

Herrington and Klein,¹⁶ in a systematic review, noted similar findings in multiple studies of tamoxifen, with decreases in total cholesterol ranging from 7% to 17% and decreases in low-density lipoprotein cholesterol ranging from 10% to 28%. However, they found no change in high-density lipoprotein cholesterol concentrations or in the cardiovascular mortality rate.

The ATLAS trial¹⁰ revealed a relative risk reduction of 0.76 (95% confidence interval [CI] 0.60–0.95, P = .02) in ischemic heart disease for women who took tamoxifen for 10 years compared with 5 years. We calculate that ischemic heart disease occurred in 163 (2.5%) of 6,440 women who took tamoxifen for 5 years compared with 127 (1.9%) of 6,454 women who took it for 10 years, a 0.6% absolute risk reduction, NNT = 167.

Adverse effects of tamoxifen

Uterine neoplasia. Women taking tamoxifen have a 2.5-fold increased risk of endometrial cancer.¹⁴ Tamoxifen also increases the risk of benign uterine disease such as endometrial hyperplasia and polyps. As many as 39% of women taking tamoxifen will have evidence of benign uterine changes on pathology.¹⁷ Other adverse effects:

Venous thromboembolism (the risk of pulmonary embolism is increased approximately threefold¹⁴)

Cataracts (there is a slight increase in cataract diagnosis in tamoxifen users)

Vasomotor symptoms, which limit the use of tamoxifen in many women.

Ideal candidate for tamoxifen

The ideal candidate for tamoxifen is a woman with breast cancer that is estrogen receptor-positive and who has a history of osteopenia or osteoporosis and no risk factors for venous thromboembolism.

Raloxifene, a second-generation ERAA, was first approved for preventing and treating osteoporosis and later for reducing the risk of invasive estrogen receptor-positive breast cancer in postmenopausal women.

Trials of raloxifene for osteoporosis

The MORE trial (Multiple Outcomes of Raloxifene)¹⁸ was a large multicenter randomized double-blind study. Raloxifene recipients showed a significant increase in bone mineral density in the lumbar spine and femoral neck at year 3 (P < .001) compared with those receiving placebo. Even after only 1 year of treatment, raloxifene significantly reduced the risk of new fractures, despite only modest gains in bone mineral density. After 3 years of treatment, new clinical vertebral fractures had occurred in 3.5% of the placebo group compared with 2.1% of the group receiving raloxifene 60 mg.¹⁹ Relative risk reductions were similar in women who had already had a clinical vertebral fracture at baseline, whose absolute risk is higher. However, no significant effect was seen on the incidence of hip or nonvertebral fractures.

The CORE trial (Continuing Outcomes Relevant to Raloxifene)²⁰ extended the treatment of the women enrolled in the MORE trial another 4 years and found that the benefit of raloxifene with regard to bone mineral density persisted with continued use.

Trials of raloxifene for breast cancer prevention

The MORE trial,²¹ in postmenopausal women with osteoporosis included breast cancer as a secondary end point, and raloxifene was shown to decrease the incidence of invasive breast cancer. At a median of 40 months, invasive breast cancer had arisen in 13 (0.25%) of the 5,129 women assigned to raloxifene and 27 (1.0%) of the 2,576 women assigned to placebo. The authors calculated that 126 women would need to be treated to prevent 1 case of breast cancer.

The CORE trial,²² as noted, extended the treatment of the women enrolled in the MORE trial another 4 years. The risk of any invasive breast cancer in postmenopausal women with osteoporosis was significantly reduced by 59% after 8 years, and the risk of estrogen receptor-positive invasive breast cancer was reduced by 66%.

There is evidence that raloxifene’s effect on breast cancer risk persists after discontinuation of use.²³

Does raloxifene reduce mortality?

Grady et al²⁴ studied the effect of raloxifene on all-cause mortality in a pooled analysis of mortality data from the MORE, CORE, and Raloxifene Use for the Heart (RUTH)²⁵ trials. In older postmenopausal women, the rate of all-cause mortality was 8.65% in those taking placebo compared with 7.88% in those taking raloxifene 60 mg daily—10% lower. The mechanism behind the lower mortality rate is unclear, and Grady et al recommend that the finding be interpreted with caution.

Trials of raloxifene for heart protection

The RUTH trial²⁵ was a 5.6-year study undertaken to study the effects of raloxifene on coronary outcomes and invasive breast cancer in postmenopausal women. Results were mixed. Active treatment:

• Did not significantly affect the risk of coronary artery disease compared with placebo
• Significantly decreased the risk of invasive breast cancer
• Significantly decreased the risk of clinical vertebral fractures
• Increased the risk of fatal stroke (59 vs 39 events, hazard ratio 1.49, 95% CI 1.00–2.24) and venous thromboembolism (103 vs 71 events, hazard ratio 1.44, 95% CI 1.06–1.95).

The STAR trial (Study of Tamoxifen and Raloxifene)^26,27 compared raloxifene and tamoxifen in postmenopausal women at increased risk of breast cancer. Women were randomized to receive either tamoxifen 20 mg or raloxifene 60 mg for 5 years. Results:

• No difference in the number of new cases of invasive breast cancer between the groups
• Fewer cases of noninvasive breast cancer in the tamoxifen group, but the difference was not statistically significant
• Fewer cases of uterine cancer in the raloxifene group, annual incidence rates 0.125% vs 0.199%, absolute risk reduction 0.74%, NNT 1,351, relative risk with raloxifene 0.62, 95% CI 0.30–0.50
• Fewer thromboembolic events with raloxifene
• Fewer cataracts with raloxifene.

Adverse effects of raloxifene

Raloxifene increases the risk of venous thromboembolism and stroke in women at high risk of coronary artery disease.¹⁹

Ideal candidates for raloxifene

Postmenopausal women with osteopenia or osteoporosis and a higher risk of breast cancer who have minimal to no vasomotor symptoms or genitourinary syndrome of menopause are good candidates for raloxifene. Raloxifene is also a good choice for women who have genitourinary syndrome of menopause treated with local vaginal estrogen. Raloxifene has no effect on vasomotor symptoms or genitourinary syndrome of menopause.

Although ospemifene does not have the steroid structure of estrogen, it acts as an estrogen agonist specifically in the vaginal mucosa and an antagonist in other tissues.²⁸ It has been shown on Papanicolaou smears to reduce the number of parabasal cells and increase the number of intermediate and superficial cells after 3 months of treatment.²⁹

Ospemifene 60 mg taken orally with food is approved by the FDA to treat genitourinary syndrome of menopause.

Why ospemifene is needed

First-line treatment options for genitourinary syndrome of menopause include over-the-counter lubricants. However, there is no evidence that these products reverse vaginal atrophy,³⁰ and many women report no relief of symptoms with them.

While various local estrogen preparations positively affect genitourinary syndrome of menopause, some of them can be messy, which can limit-long term adherence.

In one of the largest surveys on genitourinary syndrome of menopause (the REVIVE survey—the Real Women’s View of Treatment Options for Menopausal Vaginal Changes²⁹), 59% of women reported that their vaginal symptoms negatively affected sexual activity. The problem affects not only the patient but also her sexual partner.³¹ Another large study showed that 38% of women and 39% of male partners reported that it had a worse-than-expected impact on their intimate relationships.³¹

Genitourinary syndrome of menopause also makes pelvic examinations difficult, may worsen or exacerbate cystitis, and may increase urinary tract infections.

Trials of ospemifene for genitourinary syndrome of menopause

To date, 3 randomized, double-blind clinical trials have demonstrated ospemifene 60 mg to be superior to placebo in treating genitourinary syndrome of menopause. Two were short-term (12-week) and showed significant positive changes in the percent of superficial cells, vaginal pH (lower is better), and number of parabasal cells, along with improvements in the Likert rating of both vaginal dryness and dyspareunia.^32,33

A long-term (52-week) randomized placebo-controlled trial compared ospemifene and placebo and showed significant improvement in vaginal maturation index and pH at weeks 12 and 52.³⁴ Other outcome measures included petechiae, pallor, friability, erythema, and dryness, all of which improved from baseline (P < .001). At the end of the trial, 80% of the patients who received ospemifene had no vaginal atrophy.

No serious adverse events were noted in any of the clinical trials to date, and a systemic review and meta-analysis demonstrated ospemifene to be safe and efficacious.³⁵ The most frequently reported reasons for discontinuation were hot flashes, vaginal discharge, muscle spasms, and hyperhidrosis, but the rates of these effects were similar to those with placebo.

Trial of ospemifene’s effect on bone turnover

As an estrogen receptor agonist in bone, ospemifene decreases the levels of bone turnover markers in postmenopausal women.³⁶ A study found ospemifene to be about as effective as raloxifene in suppressing bone turnover,³⁷ but ospemifene does not carry FDA approval for preventing or treating osteoporosis.

Other effects

In experiments in rats, the incidence of breast cancer appears to be lower with ospemifene, and the higher the dose, the lower the incidence.³⁸

Ospemifene also has antagonistic effects on uterine tissue, and no cases of endometrial hyperplasia or carcinoma have been reported in short-term or long-term studies.³⁵

Ospemifene has no effect however on vasomotor symptoms and may in fact worsen vasomotor symptoms in women suffering with hot flashes and night sweats. Further investigation into its long-term safety and effects on breast tissue and bone would provide more insight.

Ideal candidates for ospemifene

Ospemifene could help postmenopausal women with genitourinary syndrome of menopause for whom over-the-counter lubricants fail, who dislike local vaginal estrogen, or who decline systemic hormone therapy, and who do not meet the criteria for treatment with systemic hormone therapy.

CONJUGATED ESTROGENS AND BAZEDOXIFENE COMBINATION

A combination agent consisting of conjugated estrogens 0.45 mg plus bazedoxifene 20 mg has been approved by the FDA for treating moderate to severe vasomotor symptoms associated with menopause and also for preventing postmenopausal osteoporosis in women who have an intact uterus.

Trials of estrogen-bazedoxifene for vasomotor symptoms

The Selective Estrogen Menopause and Response to Therapy (SMART) trials^39,40 were a series of randomized, double-blind, placebo-controlled phase 3 studies evaluating the efficacy and safety of the estrogen-bazedoxifene combination in postmenopausal women.

The SMART-2 trial³⁹ evaluated the combination of conjugated estrogens (either 0.45 mg or 0.625) plus bazedoxifene 20 mg and found both dosages significantly reduced the number and severity of hot flashes at weeks 4 and 12 (P < .001). At week 12, the combination with 0.45 mg of estrogen reduced vasomotor symptoms from baseline by 74% (10.3 hot flashes per week at baseline vs 2.8 at week 12); the combination with 0.625 mg of estrogen reduced vasomotor symptoms by 80% (10.4 vs 2.4 flashes); and placebo reduced them by 51% (10.5 vs 5.4 flashes).

For bone density. The SMART-1 trial⁴⁰ showed that the estrogen-bazedoxifene combination in both estrogen dosages significantly increased mean lumbar spine bone mineral density (P < .001) and total hip bone mineral density (P < .05) from baseline at 12 and 24 months compared with placebo. Increases in density tended to be higher with the higher estrogen dose (0.625 mg), but less with higher doses of bazedoxifene.⁴¹ At 24 months, the increase in bone mineral density was even greater than in women treated with raloxifene.⁴² However, the effect of estrogen-bazedoxifene on the incidence of fractures remains to be studied.

For genitourinary syndrome of menopause. The SMART-3 trial showed that treatment with conjugated estrogens plus bazedoxifene (0.45/20 mg or 0.625/20 mg) was more effective than placebo in increasing the percent of superficial and intermediate cells and decreased the number of parabasal cells at 12 weeks compared with placebo (P < .01).⁴³ Both doses also significantly decreased the mean vaginal pH and improved vaginal dryness.

Patients treated with estrogen-bazedoxifene for a minimum of 12 weeks in a double-blind placebo-controlled study also showed a significant improvement in sexual function and quality-of-life measurements based on 3 well-defined scales, which included ease of lubrication, satisfaction with treatment, control of hot flashes, and sleep parameters.⁴³

Low rates of side effects

To evaluate this regimen’s antagonistic effects on uterine tissue, endometrial hyperplasia was diagnosed by blinded pathologists using endometrial biopsies taken at 6, 12, and 24 months or more if cancer was a suspected diagnosis. At 12 and 24 months of treatment, the incidence of hyperplasia with bazedoxifene 20 or 40 mg at doses of either 0.45 or 0.625 mg of conjugated estrogens was less than 1%, which was similar to placebo rates over the 24 months.⁴⁴ The lowest dose studied, bazedoxifene 10 mg, did not prevent hyperplasia with conjugated estrogens 0.45 or 0.625 mg, and its use was discontinued.

Rates of amenorrhea with bazedoxifene 20 or 40 mg and conjugated estrogens 0.45 or 0.625 mg were very favorable (83%–93%) and similar to those with placebo.⁴⁵ For women with continued bleeding on hormone therapy requiring multiple evaluations, or for women who won’t accept the risk of bleeding on hormone therapy, conjugated estrogens and bazedoxifene may be a sustainable option. However, any woman with abnormal bleeding should undergo prompt immediate evaluation.

A typical side effect of estrogen replacement therapy is breast tenderness. For women seeking vasomotor symptom treatment but who experience breast tenderness, this may be a deterrent from continuing hormone therapy. As shown in the SMART-1 and SMART-2 trials,⁴⁶ conjugated estrogens and bazedoxifene did not cause an increase in breast tenderness, which may enhance medication adherence.

Ideal candidates for conjugated estrogens plus bazedoxifene

This product could help postmenopausal women who have an intact uterus and are suffering with moderate to severe vasomotor symptoms and genitourinary syndrome of menopause who cannot tolerate the side effects of hormone therapy such as bleeding, bloating, or breast tenderness, or who prefer to take an estrogen but without a progestin. It is also ideal for women at higher risk of osteoporosis.

WHO SHOULD GET WHAT?

Not all postmenopausal women have vasomotor symptoms, genitourinary syndrome of menopause, or bone loss. For those who do, standard hormone therapy is an option.

For those who have symptoms and a lower threshold of side effects such as breast tenderness and vaginal bleeding, a combination of an estrogen plus an ERAA (eg, bazedoxifene) is an option.

For women who have no vasomotor symptoms but do have genitourinary syndrome of menopause and don’t want local vaginal treatment, ospemifene is an option.

For women with no vasomotor symptoms but who have bone loss and increased risk of estrogen receptor-positive breast cancer, raloxifene is a good option.

Both premenopausal and postmenopausal women who are at increased risk for breast cancer should be considered for tamoxifen chemoprevention. Postmenopausal women with a uterus at increased risk for breast cancer should be considered for raloxifene, as it has no uterine effect. Raloxifene is not indicated in premenopausal women.

No woman at increased risk of venous thromboembolism is a candidate for ERAA treatment or for oral estrogen. However, the clinician has multiple options to improve quality of life and work productivity and reduce office visits of women at midlife, especially when they are individually assessed and treated.

More and more consumers are using wearable devices and smartphones to monitor and measure various body functions, including sleep. Many patients now present their providers with sleep data obtained from their phones and other devices. But can these devices provide valid, useful clinical information?

This article describes common sleep tracking devices available to consumers and the mechanisms the devices probably use to distinguish sleep from wakefulness (their algorithms are secret), the studies evaluating the validity of device manufacturers’ claims, and their clinical utility and limitations.

DEVICES ARE COMMON

Close to 1 in 10 adults over age 18 owns an activity tracker, and sales are projected to reach $50 billion by 2018.¹ Even more impressive, close to 69% of Americans own a smartphone,¹ and more than half use it as an alarm clock.²

At the same time that these devices have become so popular, sleep medicine has come of age, and experts have been pushing to improve people’s sleep and increase awareness of sleep disorders.^3,4 While the technology has significantly advanced, adoption of data from these devices for clinical evaluation has been limited. Studies examining the validity of these devices have only recently been conducted, and companies that make the devices have not been forthcoming with details of the specific algorithms they use to tell if the patient is asleep or awake or what stage of sleep the patient is in.

WHAT ARE THESE DEVICES?

Consumer tracking devices that claim to measure sleep are easily available for purchase and include wearable fitness trackers such as Fitbit, Jawbone UP, and Nike+ Fuelband. Other sleep tracking devices are catalogued by Ko et al.⁵ Various smartphone applications (apps) are also available.

Fitness trackers, usually worn as a wrist band, are primarily designed to measure movement and activity, but manufacturers now claim the trackers can also measure sleep. Collected data are available for the user to review the following day. In most cases, these trackers display sleep and wake times; others also claim to record sound sleep, light sleep, and the number and duration of awakenings. Most fitness trackers have complementary apps available for download that graphically display the data on smartphones and interact with social media to allow users to post their sleep and activity data.

More than 500 sleep-related apps are available for download to smartphones in the iTunes app store⁵; the Sleep Cycle alarm clock app was among the top 5 sleep-tracking apps downloaded in 2014.⁶ Because sleep data collection relies on the smartphone being placed on the user’s mattress, movements of bed partners, pets, and bedding may interfere with results. In most cases, the apps display data in a format similar to that of fitness trackers. Some claim to determine the optimal sleep phase for the alarm to wake the user.

HOW DOES THE TECHNOLOGY WORK?

Older activity-tracking devices used single-channel electroencephalographic recordings or multiple physiologic channels such as galvanic skin response, skin temperature, and heat flux to measure activity to determine transitions between periods of sleep and wakefulness.^7,8

None of the currently available consumer sleep tracking devices discloses the exact mechanisms used to measure sleep and wakefulness, but most appear to rely on 3-axis accelerometers,⁹ ie, microelectromechanical devices that measure front-to-back, side-to-side, and up-and-down motion and convert the data into an activity count. Activity counts are acquired over 30- or 60-second intervals and are entered into algorithms that determine if the pattern indicates that the patient is awake or asleep. This is the same method that actigraphy uses to evaluate sleep, but most actigraphs used in medicine disclose their mechanisms and provide clinicians with the option of using various validated algorithms to classify the activity counts into sleep or awake periods.^9–11

ARE THE MEASURES VALID?

Only a few studies have examined the validity and accuracy of current fitness trackers and apps for measuring sleep.

The available studies are difficult to compare; most have been small and used different actigraphy devices for comparison. Some tested healthy volunteers, others included people with suspected or confirmed sleep disorders, and some had both types of participants. In many studies, the device was compared with polysomnography for only 1 night, making the “first-night effect” likely to be a confounding factor, as people tend to sleep worse during the first night of testing. Technical failures for the devices were noted in some studies.¹² In addition, some currently used apps may use different platforms than the devices used in these studies, limiting the extrapolation of results.

As with fitness trackers, few studies have been done to examine the validity of smartphone apps.⁵ Findings of 3 studies are summarized in Table 2.^17–19 In addition to tracking the duration and depth of sleep, some apps purport to detect snoring, sleep apnea, and periodic limb movements of sleep. Discussion of these apps is beyond the scope of this review.

ARE THE DEVICES CLINICALLY USEFUL?

Although a thorough history remains the cornerstone of a good evaluation of sleep problems, testing is sometimes essential, and in certain situations, objective data can complement the history and clarify the diagnosis.

Polysomnography remains the gold standard for telling when the patient is asleep vs awake, diagnosing sleep-disordered breathing, detecting periodic limb movements and parasomnias, and aiding in the diagnosis of narcolepsy.

Actigraphy, which uses technology similar to fitness trackers, can help distinguish sleep from wakefulness, reveal erratic sleep schedules, and help diagnose circadian rhythm sleep disorders. In patients with insomnia, actigraphy can help determine daily sleep patterns and response to treatment.²⁰ It can be especially useful for patients who cannot provide a clear history, eg, children and those with developmental disabilities or cognitive dysfunction.

Consumer sleep tracking devices, like actigraphy, are portable and unobtrusive, providing a way to measure sleep duration and demonstrate sleep patterns in a patient’s natural environment. Being more accessible, cheaper, and less time-consuming than clinical tests, the commercially available devices could be clinically useful in some situations, eg, for monitoring overall sleep patterns to look for circadian sleep-wake disorders, commonly seen in shift workers (shift work disorder) or adolescents (delayed sleep-wake phase disorder); or in patients with poor motivation to maintain a sleep diary. Because of their poor performance in clinical trials, they should not be relied upon to distinguish sleep from wakefulness, quantify the amount of sleep, determine sleep stages, and awaken patients exclusively from light sleep.

Discerning poor sleep hygiene from insomnia

Patients with insomnia tend to take longer to go to sleep (have longer sleep latencies), wake up more (have more disturbed sleep with increased awakenings), and have shorter sleep times with reduced sleep efficiencies.²¹ Sleep tracking devices tend to be less accurate for patients with short sleep duration and disturbed sleep, limiting their usefulness in this group. Furthermore, patients with insomnia tend to underestimate their sleep time and overestimate sleep latency; some devices also tend to overestimate the time to fall asleep, reinforcing this common error made by patients.^22,23

On the other hand, data from sleep tracking devices could help distinguish poor sleep hygiene from an insomnia disorder. For example, the data may indicate that a patient has poor sleep habits, such as taking long daytime naps or having significantly variable time in and out of bed from day to day. The total times asleep and awake in the middle of the night may also be substantially different on each night, which would also possibly indicate poor sleep hygiene.

Detecting circadian rhythms

A device may show that a patient has a clear circadian preference that is not in line with his or her daily routines, suggesting an underlying circadian rhythm sleep-wake disorder. This may be evident by bedtimes and wake times that are consistent but substantially out of sync with one’s social or occupational needs.

Measuring overall sleep duration

In people with normal sleep, fitness trackers perform reasonably well for measuring overall sleep duration. This information could be used to assess a patient with daytime sleepiness and fatigue to evaluate insufficient sleep as an etiologic factor.

Table 3 summarizes how to evaluate the data from sleep apps and fitness tracking devices for clinical use. While these features of consumer sleep tracking devices could conceivably help in the above clinical scenarios, further validation of devices in clinical populations is necessary before their use can be recommended without reservation.

ADVISING PATIENTS

Patients sometimes present to clinicians with concerns about the duration of sleep time and time spent in various sleep stages as delineated by their sleep tracking devices. Currently, these devices do not appear to be able to adequately distinguish various sleep stages, and in many users, they can substantially underestimate or overestimate sleep parameters such as time taken to fall asleep or duration of awakenings in the middle of the night. Patients can be reassured about this lack of evidence and should be advised to not place too much weight on such data alone.

Sleep “goals” set by many devices have not been scientifically validated. People without sleep problems should be discouraged from making substantial changes to their routines to accommodate sleep targets set by the devices. Patients should be counseled about the pitfalls of the data and can be reassured that little evidence suggests that time spent in various sleep stages correlates with adverse daytime consequences or with poor health outcomes.

Some of the apps used as alarm clocks claim to be able to tell what stage of sleep people are in and wait to awaken them until they are in a light stage, which is less jarring than being awakened from a deep stage, but the evidence for this is unclear. In the one study that tested this claim, the app did not awaken participants from light sleep more often than is likely to occur by chance.¹⁷ The utility of these apps as personalized alarm clocks is still extremely limited, and patients should be counseled to obtain an adequate amount of sleep rather than rely on devices to awaken them during specific sleep stages.

The rates for discontinuing the use of these devices are high, which could limit their utility. Some surveys have shown that close to 50% of users stop using fitness trackers; 33% stop using them within 6 months of obtaining the device.²⁴ Also, there is little evidence that close monitoring of sleep results in behavior changes or improved sleep duration. Conversely, the potential harms of excessive monitoring of one’s sleep are currently unknown.

More and more consumers are using wearable devices and smartphones to monitor and measure various body functions, including sleep. Many patients now present their providers with sleep data obtained from their phones and other devices. But can these devices provide valid, useful clinical information?

This article describes common sleep tracking devices available to consumers and the mechanisms the devices probably use to distinguish sleep from wakefulness (their algorithms are secret), the studies evaluating the validity of device manufacturers’ claims, and their clinical utility and limitations.

DEVICES ARE COMMON

Close to 1 in 10 adults over age 18 owns an activity tracker, and sales are projected to reach $50 billion by 2018.¹ Even more impressive, close to 69% of Americans own a smartphone,¹ and more than half use it as an alarm clock.²

At the same time that these devices have become so popular, sleep medicine has come of age, and experts have been pushing to improve people’s sleep and increase awareness of sleep disorders.^3,4 While the technology has significantly advanced, adoption of data from these devices for clinical evaluation has been limited. Studies examining the validity of these devices have only recently been conducted, and companies that make the devices have not been forthcoming with details of the specific algorithms they use to tell if the patient is asleep or awake or what stage of sleep the patient is in.

WHAT ARE THESE DEVICES?

Consumer tracking devices that claim to measure sleep are easily available for purchase and include wearable fitness trackers such as Fitbit, Jawbone UP, and Nike+ Fuelband. Other sleep tracking devices are catalogued by Ko et al.⁵ Various smartphone applications (apps) are also available.

Fitness trackers, usually worn as a wrist band, are primarily designed to measure movement and activity, but manufacturers now claim the trackers can also measure sleep. Collected data are available for the user to review the following day. In most cases, these trackers display sleep and wake times; others also claim to record sound sleep, light sleep, and the number and duration of awakenings. Most fitness trackers have complementary apps available for download that graphically display the data on smartphones and interact with social media to allow users to post their sleep and activity data.

More than 500 sleep-related apps are available for download to smartphones in the iTunes app store⁵; the Sleep Cycle alarm clock app was among the top 5 sleep-tracking apps downloaded in 2014.⁶ Because sleep data collection relies on the smartphone being placed on the user’s mattress, movements of bed partners, pets, and bedding may interfere with results. In most cases, the apps display data in a format similar to that of fitness trackers. Some claim to determine the optimal sleep phase for the alarm to wake the user.

HOW DOES THE TECHNOLOGY WORK?

Older activity-tracking devices used single-channel electroencephalographic recordings or multiple physiologic channels such as galvanic skin response, skin temperature, and heat flux to measure activity to determine transitions between periods of sleep and wakefulness.^7,8

None of the currently available consumer sleep tracking devices discloses the exact mechanisms used to measure sleep and wakefulness, but most appear to rely on 3-axis accelerometers,⁹ ie, microelectromechanical devices that measure front-to-back, side-to-side, and up-and-down motion and convert the data into an activity count. Activity counts are acquired over 30- or 60-second intervals and are entered into algorithms that determine if the pattern indicates that the patient is awake or asleep. This is the same method that actigraphy uses to evaluate sleep, but most actigraphs used in medicine disclose their mechanisms and provide clinicians with the option of using various validated algorithms to classify the activity counts into sleep or awake periods.^9–11

ARE THE MEASURES VALID?

Only a few studies have examined the validity and accuracy of current fitness trackers and apps for measuring sleep.

The available studies are difficult to compare; most have been small and used different actigraphy devices for comparison. Some tested healthy volunteers, others included people with suspected or confirmed sleep disorders, and some had both types of participants. In many studies, the device was compared with polysomnography for only 1 night, making the “first-night effect” likely to be a confounding factor, as people tend to sleep worse during the first night of testing. Technical failures for the devices were noted in some studies.¹² In addition, some currently used apps may use different platforms than the devices used in these studies, limiting the extrapolation of results.

As with fitness trackers, few studies have been done to examine the validity of smartphone apps.⁵ Findings of 3 studies are summarized in Table 2.^17–19 In addition to tracking the duration and depth of sleep, some apps purport to detect snoring, sleep apnea, and periodic limb movements of sleep. Discussion of these apps is beyond the scope of this review.

ARE THE DEVICES CLINICALLY USEFUL?

Although a thorough history remains the cornerstone of a good evaluation of sleep problems, testing is sometimes essential, and in certain situations, objective data can complement the history and clarify the diagnosis.

Polysomnography remains the gold standard for telling when the patient is asleep vs awake, diagnosing sleep-disordered breathing, detecting periodic limb movements and parasomnias, and aiding in the diagnosis of narcolepsy.

Actigraphy, which uses technology similar to fitness trackers, can help distinguish sleep from wakefulness, reveal erratic sleep schedules, and help diagnose circadian rhythm sleep disorders. In patients with insomnia, actigraphy can help determine daily sleep patterns and response to treatment.²⁰ It can be especially useful for patients who cannot provide a clear history, eg, children and those with developmental disabilities or cognitive dysfunction.

Consumer sleep tracking devices, like actigraphy, are portable and unobtrusive, providing a way to measure sleep duration and demonstrate sleep patterns in a patient’s natural environment. Being more accessible, cheaper, and less time-consuming than clinical tests, the commercially available devices could be clinically useful in some situations, eg, for monitoring overall sleep patterns to look for circadian sleep-wake disorders, commonly seen in shift workers (shift work disorder) or adolescents (delayed sleep-wake phase disorder); or in patients with poor motivation to maintain a sleep diary. Because of their poor performance in clinical trials, they should not be relied upon to distinguish sleep from wakefulness, quantify the amount of sleep, determine sleep stages, and awaken patients exclusively from light sleep.

Discerning poor sleep hygiene from insomnia

Patients with insomnia tend to take longer to go to sleep (have longer sleep latencies), wake up more (have more disturbed sleep with increased awakenings), and have shorter sleep times with reduced sleep efficiencies.²¹ Sleep tracking devices tend to be less accurate for patients with short sleep duration and disturbed sleep, limiting their usefulness in this group. Furthermore, patients with insomnia tend to underestimate their sleep time and overestimate sleep latency; some devices also tend to overestimate the time to fall asleep, reinforcing this common error made by patients.^22,23

On the other hand, data from sleep tracking devices could help distinguish poor sleep hygiene from an insomnia disorder. For example, the data may indicate that a patient has poor sleep habits, such as taking long daytime naps or having significantly variable time in and out of bed from day to day. The total times asleep and awake in the middle of the night may also be substantially different on each night, which would also possibly indicate poor sleep hygiene.

Detecting circadian rhythms

A device may show that a patient has a clear circadian preference that is not in line with his or her daily routines, suggesting an underlying circadian rhythm sleep-wake disorder. This may be evident by bedtimes and wake times that are consistent but substantially out of sync with one’s social or occupational needs.

Measuring overall sleep duration

In people with normal sleep, fitness trackers perform reasonably well for measuring overall sleep duration. This information could be used to assess a patient with daytime sleepiness and fatigue to evaluate insufficient sleep as an etiologic factor.

Table 3 summarizes how to evaluate the data from sleep apps and fitness tracking devices for clinical use. While these features of consumer sleep tracking devices could conceivably help in the above clinical scenarios, further validation of devices in clinical populations is necessary before their use can be recommended without reservation.

ADVISING PATIENTS

Patients sometimes present to clinicians with concerns about the duration of sleep time and time spent in various sleep stages as delineated by their sleep tracking devices. Currently, these devices do not appear to be able to adequately distinguish various sleep stages, and in many users, they can substantially underestimate or overestimate sleep parameters such as time taken to fall asleep or duration of awakenings in the middle of the night. Patients can be reassured about this lack of evidence and should be advised to not place too much weight on such data alone.

Sleep “goals” set by many devices have not been scientifically validated. People without sleep problems should be discouraged from making substantial changes to their routines to accommodate sleep targets set by the devices. Patients should be counseled about the pitfalls of the data and can be reassured that little evidence suggests that time spent in various sleep stages correlates with adverse daytime consequences or with poor health outcomes.

Some of the apps used as alarm clocks claim to be able to tell what stage of sleep people are in and wait to awaken them until they are in a light stage, which is less jarring than being awakened from a deep stage, but the evidence for this is unclear. In the one study that tested this claim, the app did not awaken participants from light sleep more often than is likely to occur by chance.¹⁷ The utility of these apps as personalized alarm clocks is still extremely limited, and patients should be counseled to obtain an adequate amount of sleep rather than rely on devices to awaken them during specific sleep stages.

The rates for discontinuing the use of these devices are high, which could limit their utility. Some surveys have shown that close to 50% of users stop using fitness trackers; 33% stop using them within 6 months of obtaining the device.²⁴ Also, there is little evidence that close monitoring of sleep results in behavior changes or improved sleep duration. Conversely, the potential harms of excessive monitoring of one’s sleep are currently unknown.

More and more consumers are using wearable devices and smartphones to monitor and measure various body functions, including sleep. Many patients now present their providers with sleep data obtained from their phones and other devices. But can these devices provide valid, useful clinical information?

This article describes common sleep tracking devices available to consumers and the mechanisms the devices probably use to distinguish sleep from wakefulness (their algorithms are secret), the studies evaluating the validity of device manufacturers’ claims, and their clinical utility and limitations.

DEVICES ARE COMMON

Close to 1 in 10 adults over age 18 owns an activity tracker, and sales are projected to reach $50 billion by 2018.¹ Even more impressive, close to 69% of Americans own a smartphone,¹ and more than half use it as an alarm clock.²

At the same time that these devices have become so popular, sleep medicine has come of age, and experts have been pushing to improve people’s sleep and increase awareness of sleep disorders.^3,4 While the technology has significantly advanced, adoption of data from these devices for clinical evaluation has been limited. Studies examining the validity of these devices have only recently been conducted, and companies that make the devices have not been forthcoming with details of the specific algorithms they use to tell if the patient is asleep or awake or what stage of sleep the patient is in.

WHAT ARE THESE DEVICES?

Consumer tracking devices that claim to measure sleep are easily available for purchase and include wearable fitness trackers such as Fitbit, Jawbone UP, and Nike+ Fuelband. Other sleep tracking devices are catalogued by Ko et al.⁵ Various smartphone applications (apps) are also available.

Fitness trackers, usually worn as a wrist band, are primarily designed to measure movement and activity, but manufacturers now claim the trackers can also measure sleep. Collected data are available for the user to review the following day. In most cases, these trackers display sleep and wake times; others also claim to record sound sleep, light sleep, and the number and duration of awakenings. Most fitness trackers have complementary apps available for download that graphically display the data on smartphones and interact with social media to allow users to post their sleep and activity data.

More than 500 sleep-related apps are available for download to smartphones in the iTunes app store⁵; the Sleep Cycle alarm clock app was among the top 5 sleep-tracking apps downloaded in 2014.⁶ Because sleep data collection relies on the smartphone being placed on the user’s mattress, movements of bed partners, pets, and bedding may interfere with results. In most cases, the apps display data in a format similar to that of fitness trackers. Some claim to determine the optimal sleep phase for the alarm to wake the user.

HOW DOES THE TECHNOLOGY WORK?

Older activity-tracking devices used single-channel electroencephalographic recordings or multiple physiologic channels such as galvanic skin response, skin temperature, and heat flux to measure activity to determine transitions between periods of sleep and wakefulness.^7,8

None of the currently available consumer sleep tracking devices discloses the exact mechanisms used to measure sleep and wakefulness, but most appear to rely on 3-axis accelerometers,⁹ ie, microelectromechanical devices that measure front-to-back, side-to-side, and up-and-down motion and convert the data into an activity count. Activity counts are acquired over 30- or 60-second intervals and are entered into algorithms that determine if the pattern indicates that the patient is awake or asleep. This is the same method that actigraphy uses to evaluate sleep, but most actigraphs used in medicine disclose their mechanisms and provide clinicians with the option of using various validated algorithms to classify the activity counts into sleep or awake periods.^9–11

ARE THE MEASURES VALID?

Only a few studies have examined the validity and accuracy of current fitness trackers and apps for measuring sleep.

The available studies are difficult to compare; most have been small and used different actigraphy devices for comparison. Some tested healthy volunteers, others included people with suspected or confirmed sleep disorders, and some had both types of participants. In many studies, the device was compared with polysomnography for only 1 night, making the “first-night effect” likely to be a confounding factor, as people tend to sleep worse during the first night of testing. Technical failures for the devices were noted in some studies.¹² In addition, some currently used apps may use different platforms than the devices used in these studies, limiting the extrapolation of results.

As with fitness trackers, few studies have been done to examine the validity of smartphone apps.⁵ Findings of 3 studies are summarized in Table 2.^17–19 In addition to tracking the duration and depth of sleep, some apps purport to detect snoring, sleep apnea, and periodic limb movements of sleep. Discussion of these apps is beyond the scope of this review.

ARE THE DEVICES CLINICALLY USEFUL?

Although a thorough history remains the cornerstone of a good evaluation of sleep problems, testing is sometimes essential, and in certain situations, objective data can complement the history and clarify the diagnosis.

Polysomnography remains the gold standard for telling when the patient is asleep vs awake, diagnosing sleep-disordered breathing, detecting periodic limb movements and parasomnias, and aiding in the diagnosis of narcolepsy.

Actigraphy, which uses technology similar to fitness trackers, can help distinguish sleep from wakefulness, reveal erratic sleep schedules, and help diagnose circadian rhythm sleep disorders. In patients with insomnia, actigraphy can help determine daily sleep patterns and response to treatment.²⁰ It can be especially useful for patients who cannot provide a clear history, eg, children and those with developmental disabilities or cognitive dysfunction.

Consumer sleep tracking devices, like actigraphy, are portable and unobtrusive, providing a way to measure sleep duration and demonstrate sleep patterns in a patient’s natural environment. Being more accessible, cheaper, and less time-consuming than clinical tests, the commercially available devices could be clinically useful in some situations, eg, for monitoring overall sleep patterns to look for circadian sleep-wake disorders, commonly seen in shift workers (shift work disorder) or adolescents (delayed sleep-wake phase disorder); or in patients with poor motivation to maintain a sleep diary. Because of their poor performance in clinical trials, they should not be relied upon to distinguish sleep from wakefulness, quantify the amount of sleep, determine sleep stages, and awaken patients exclusively from light sleep.

Discerning poor sleep hygiene from insomnia

Patients with insomnia tend to take longer to go to sleep (have longer sleep latencies), wake up more (have more disturbed sleep with increased awakenings), and have shorter sleep times with reduced sleep efficiencies.²¹ Sleep tracking devices tend to be less accurate for patients with short sleep duration and disturbed sleep, limiting their usefulness in this group. Furthermore, patients with insomnia tend to underestimate their sleep time and overestimate sleep latency; some devices also tend to overestimate the time to fall asleep, reinforcing this common error made by patients.^22,23

On the other hand, data from sleep tracking devices could help distinguish poor sleep hygiene from an insomnia disorder. For example, the data may indicate that a patient has poor sleep habits, such as taking long daytime naps or having significantly variable time in and out of bed from day to day. The total times asleep and awake in the middle of the night may also be substantially different on each night, which would also possibly indicate poor sleep hygiene.

Detecting circadian rhythms

A device may show that a patient has a clear circadian preference that is not in line with his or her daily routines, suggesting an underlying circadian rhythm sleep-wake disorder. This may be evident by bedtimes and wake times that are consistent but substantially out of sync with one’s social or occupational needs.

Measuring overall sleep duration

In people with normal sleep, fitness trackers perform reasonably well for measuring overall sleep duration. This information could be used to assess a patient with daytime sleepiness and fatigue to evaluate insufficient sleep as an etiologic factor.

Table 3 summarizes how to evaluate the data from sleep apps and fitness tracking devices for clinical use. While these features of consumer sleep tracking devices could conceivably help in the above clinical scenarios, further validation of devices in clinical populations is necessary before their use can be recommended without reservation.

ADVISING PATIENTS

Patients sometimes present to clinicians with concerns about the duration of sleep time and time spent in various sleep stages as delineated by their sleep tracking devices. Currently, these devices do not appear to be able to adequately distinguish various sleep stages, and in many users, they can substantially underestimate or overestimate sleep parameters such as time taken to fall asleep or duration of awakenings in the middle of the night. Patients can be reassured about this lack of evidence and should be advised to not place too much weight on such data alone.

Sleep “goals” set by many devices have not been scientifically validated. People without sleep problems should be discouraged from making substantial changes to their routines to accommodate sleep targets set by the devices. Patients should be counseled about the pitfalls of the data and can be reassured that little evidence suggests that time spent in various sleep stages correlates with adverse daytime consequences or with poor health outcomes.

Some of the apps used as alarm clocks claim to be able to tell what stage of sleep people are in and wait to awaken them until they are in a light stage, which is less jarring than being awakened from a deep stage, but the evidence for this is unclear. In the one study that tested this claim, the app did not awaken participants from light sleep more often than is likely to occur by chance.¹⁷ The utility of these apps as personalized alarm clocks is still extremely limited, and patients should be counseled to obtain an adequate amount of sleep rather than rely on devices to awaken them during specific sleep stages.

The rates for discontinuing the use of these devices are high, which could limit their utility. Some surveys have shown that close to 50% of users stop using fitness trackers; 33% stop using them within 6 months of obtaining the device.²⁴ Also, there is little evidence that close monitoring of sleep results in behavior changes or improved sleep duration. Conversely, the potential harms of excessive monitoring of one’s sleep are currently unknown.

A 68-year-old man presented with concern about a bluish toe. Several months earlier he had undergone total aortic arch replacement and coronary artery bypass grafting. Since then his renal function had declined and he had been losing weight. 

He had hypercholesterolemia, hypertension, and a 20-pack-year smoking history. Physical examination confirmed that his right great toe was indeed bluish (Figure 1). Peripheral, neck, and abdominal vascular examinations were normal. Laboratory testing revealed:

• Serum creatinine concentration 5.15 mg/dL (reference range 0.61–1.04)
• C-reactive protein level 1.5 mg/dL (0–0.3)
• Eosinophil count 0.58 × 10⁹/L (0–0.50)
• Serum complement level normal
• Urine sediment unremarkable.

Transthoracic echocardiography revealed no evidence of vegetation, and a series of blood cultures were negative. The right toe was biopsied, and study revealed cholesterol clefts (Figure 2), confirming the diagnosis of cholesterol crystal embolism.

He was treated with prednisolone 20 mg/day, and his weight loss and renal function improved.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol embolization typically occurs after arteriography, cardiac catheterization, vascular surgery, or anticoagulant use in men over age 55 with atherosclerosis.¹ It presents with renal failure, abdominal pain, systemic symptoms, or, most commonly (in 88% of cases), skin findings.²

“Blue-toe syndrome,” characterized by tissue ischemia, is seen in 65% of patients.² Lesions can appear anywhere on the body, but most commonly on the lower extremities. Most are painful due to ischemia. The condition can progress to necrosis.

Patients may have elevated C-reactive protein, hypocomplementemia (39%), and eosinophilia (80%).^3,4 The diagnosis is confirmed only with histopathologic findings of intravascular cholesterol crystals, seen as cholesterol clefts.

The differential diagnosis includes contrast nephropathy and infectious endocarditis. However, contrast nephropathy begins to recover within several days and is not accompanied by skin lesions. Repeated blood cultures and echocardiography are useful to rule out infectious endocarditis.

Treatment includes managing cardiovascular risk factors and end-organ ischemia and preventing recurrent embolization. Surgical or endovascular treatment has been shown to be effective in decreasing the rate of further embolism.² Corticosteroid therapy is assumed to control the secondary inflammation associated with cholesterol crystal embolism.^1,5

A 68-year-old man presented with concern about a bluish toe. Several months earlier he had undergone total aortic arch replacement and coronary artery bypass grafting. Since then his renal function had declined and he had been losing weight. 

He had hypercholesterolemia, hypertension, and a 20-pack-year smoking history. Physical examination confirmed that his right great toe was indeed bluish (Figure 1). Peripheral, neck, and abdominal vascular examinations were normal. Laboratory testing revealed:

• Serum creatinine concentration 5.15 mg/dL (reference range 0.61–1.04)
• C-reactive protein level 1.5 mg/dL (0–0.3)
• Eosinophil count 0.58 × 10⁹/L (0–0.50)
• Serum complement level normal
• Urine sediment unremarkable.

Transthoracic echocardiography revealed no evidence of vegetation, and a series of blood cultures were negative. The right toe was biopsied, and study revealed cholesterol clefts (Figure 2), confirming the diagnosis of cholesterol crystal embolism.

He was treated with prednisolone 20 mg/day, and his weight loss and renal function improved.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol embolization typically occurs after arteriography, cardiac catheterization, vascular surgery, or anticoagulant use in men over age 55 with atherosclerosis.¹ It presents with renal failure, abdominal pain, systemic symptoms, or, most commonly (in 88% of cases), skin findings.²

“Blue-toe syndrome,” characterized by tissue ischemia, is seen in 65% of patients.² Lesions can appear anywhere on the body, but most commonly on the lower extremities. Most are painful due to ischemia. The condition can progress to necrosis.

Patients may have elevated C-reactive protein, hypocomplementemia (39%), and eosinophilia (80%).^3,4 The diagnosis is confirmed only with histopathologic findings of intravascular cholesterol crystals, seen as cholesterol clefts.

The differential diagnosis includes contrast nephropathy and infectious endocarditis. However, contrast nephropathy begins to recover within several days and is not accompanied by skin lesions. Repeated blood cultures and echocardiography are useful to rule out infectious endocarditis.

Treatment includes managing cardiovascular risk factors and end-organ ischemia and preventing recurrent embolization. Surgical or endovascular treatment has been shown to be effective in decreasing the rate of further embolism.² Corticosteroid therapy is assumed to control the secondary inflammation associated with cholesterol crystal embolism.^1,5

A 68-year-old man presented with concern about a bluish toe. Several months earlier he had undergone total aortic arch replacement and coronary artery bypass grafting. Since then his renal function had declined and he had been losing weight. 

He had hypercholesterolemia, hypertension, and a 20-pack-year smoking history. Physical examination confirmed that his right great toe was indeed bluish (Figure 1). Peripheral, neck, and abdominal vascular examinations were normal. Laboratory testing revealed:

• Serum creatinine concentration 5.15 mg/dL (reference range 0.61–1.04)
• C-reactive protein level 1.5 mg/dL (0–0.3)
• Eosinophil count 0.58 × 10⁹/L (0–0.50)
• Serum complement level normal
• Urine sediment unremarkable.

Transthoracic echocardiography revealed no evidence of vegetation, and a series of blood cultures were negative. The right toe was biopsied, and study revealed cholesterol clefts (Figure 2), confirming the diagnosis of cholesterol crystal embolism.

He was treated with prednisolone 20 mg/day, and his weight loss and renal function improved.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol embolization typically occurs after arteriography, cardiac catheterization, vascular surgery, or anticoagulant use in men over age 55 with atherosclerosis.¹ It presents with renal failure, abdominal pain, systemic symptoms, or, most commonly (in 88% of cases), skin findings.²

“Blue-toe syndrome,” characterized by tissue ischemia, is seen in 65% of patients.² Lesions can appear anywhere on the body, but most commonly on the lower extremities. Most are painful due to ischemia. The condition can progress to necrosis.

Patients may have elevated C-reactive protein, hypocomplementemia (39%), and eosinophilia (80%).^3,4 The diagnosis is confirmed only with histopathologic findings of intravascular cholesterol crystals, seen as cholesterol clefts.

The differential diagnosis includes contrast nephropathy and infectious endocarditis. However, contrast nephropathy begins to recover within several days and is not accompanied by skin lesions. Repeated blood cultures and echocardiography are useful to rule out infectious endocarditis.

Treatment includes managing cardiovascular risk factors and end-organ ischemia and preventing recurrent embolization. Surgical or endovascular treatment has been shown to be effective in decreasing the rate of further embolism.² Corticosteroid therapy is assumed to control the secondary inflammation associated with cholesterol crystal embolism.^1,5

On the eighth day after giving birth to monochorionic twins, a 33-year-old woman presented with pruritic erythematous papules and plaques that started on the striae of the lower abdomen and spread rapidly to the thighs and upper limbs, sparing the umbilical region (Figure 1). Histologic examination of a specimen of the abdominal plaques showed moderate superficial perivascular lymphohistiocytic infiltrate with eosinophils (Figure 2), leading to the diagnosis of polymorphic eruption of pregnancy. Oral cetirizine 10 mg/day and topical methylprednisolone cream brought complete regression of the lesions within 1 month.

DERMATOSES OF PREGNANCY

Polymorphic eruption of pregnancy—also known as pruritic urticarial papules and plaques of pregnancy¹—is a specific dermatosis of pregnancy characterized by pruritic urticarial papules on abdominal striae that usually first appear during the latter portion of the third trimester or immediately postpartum. It is more frequent in primiparous women and does not represent a risk to the mother or fetus.^2–4

The lesions tend to coalesce into plaques, spreading to the buttocks and proximal thighs. They then become more polymorphic and vesicular, with widespread nonurticated erythema and targetoid and eczematous lesions. Characteristically, the lesions spare the umbilical region. Their location within striae suggests that stretching of abdominal skin may damage the connective tissue, initiating an immune response with subsequent appearance of the eruption.^2,4

The diagnosis is mainly clinical. In some cases, skin biopsy can help to confirm the diagnosis. Histologic features are nonspecific and vary with the stage of disease, showing a superficial to mid-dermal perivascular lymphohistiocytic infiltrate with eosinophils. At earlier stages, biopsy results can show a prominent dermal edema. In later stages, epidermal changes such as spongiosis, hyperkeratosis, and parakeratosis can occur.²

As an aid to diagnosis, Table 1 lists clinical differences between various dermatoses of pregnancy.

On the eighth day after giving birth to monochorionic twins, a 33-year-old woman presented with pruritic erythematous papules and plaques that started on the striae of the lower abdomen and spread rapidly to the thighs and upper limbs, sparing the umbilical region (Figure 1). Histologic examination of a specimen of the abdominal plaques showed moderate superficial perivascular lymphohistiocytic infiltrate with eosinophils (Figure 2), leading to the diagnosis of polymorphic eruption of pregnancy. Oral cetirizine 10 mg/day and topical methylprednisolone cream brought complete regression of the lesions within 1 month.

DERMATOSES OF PREGNANCY

Polymorphic eruption of pregnancy—also known as pruritic urticarial papules and plaques of pregnancy¹—is a specific dermatosis of pregnancy characterized by pruritic urticarial papules on abdominal striae that usually first appear during the latter portion of the third trimester or immediately postpartum. It is more frequent in primiparous women and does not represent a risk to the mother or fetus.^2–4

The lesions tend to coalesce into plaques, spreading to the buttocks and proximal thighs. They then become more polymorphic and vesicular, with widespread nonurticated erythema and targetoid and eczematous lesions. Characteristically, the lesions spare the umbilical region. Their location within striae suggests that stretching of abdominal skin may damage the connective tissue, initiating an immune response with subsequent appearance of the eruption.^2,4

The diagnosis is mainly clinical. In some cases, skin biopsy can help to confirm the diagnosis. Histologic features are nonspecific and vary with the stage of disease, showing a superficial to mid-dermal perivascular lymphohistiocytic infiltrate with eosinophils. At earlier stages, biopsy results can show a prominent dermal edema. In later stages, epidermal changes such as spongiosis, hyperkeratosis, and parakeratosis can occur.²

As an aid to diagnosis, Table 1 lists clinical differences between various dermatoses of pregnancy.

On the eighth day after giving birth to monochorionic twins, a 33-year-old woman presented with pruritic erythematous papules and plaques that started on the striae of the lower abdomen and spread rapidly to the thighs and upper limbs, sparing the umbilical region (Figure 1). Histologic examination of a specimen of the abdominal plaques showed moderate superficial perivascular lymphohistiocytic infiltrate with eosinophils (Figure 2), leading to the diagnosis of polymorphic eruption of pregnancy. Oral cetirizine 10 mg/day and topical methylprednisolone cream brought complete regression of the lesions within 1 month.

DERMATOSES OF PREGNANCY

Polymorphic eruption of pregnancy—also known as pruritic urticarial papules and plaques of pregnancy¹—is a specific dermatosis of pregnancy characterized by pruritic urticarial papules on abdominal striae that usually first appear during the latter portion of the third trimester or immediately postpartum. It is more frequent in primiparous women and does not represent a risk to the mother or fetus.^2–4

The lesions tend to coalesce into plaques, spreading to the buttocks and proximal thighs. They then become more polymorphic and vesicular, with widespread nonurticated erythema and targetoid and eczematous lesions. Characteristically, the lesions spare the umbilical region. Their location within striae suggests that stretching of abdominal skin may damage the connective tissue, initiating an immune response with subsequent appearance of the eruption.^2,4

The diagnosis is mainly clinical. In some cases, skin biopsy can help to confirm the diagnosis. Histologic features are nonspecific and vary with the stage of disease, showing a superficial to mid-dermal perivascular lymphohistiocytic infiltrate with eosinophils. At earlier stages, biopsy results can show a prominent dermal edema. In later stages, epidermal changes such as spongiosis, hyperkeratosis, and parakeratosis can occur.²

As an aid to diagnosis, Table 1 lists clinical differences between various dermatoses of pregnancy.

In-hospital mobility (walking and transferring) is an important modifiable factor for posthospital functional outcomes and mortality among older adults.^1-4 In fact, daily mobility assessment has been considered for a standard clinical evaluation of the hospitalized older adult.^5,6 This would provide a ready source for targeting patients at risk for mobility impairment and identifying strategies to prevent in-hospital mobility limitation and posthospital functional decline. Despite their potential importance, mobility assessment tools have not been readily adopted in the hospital setting.

There are various ways to assess mobility in hospital settings. Mobility tracking technology (radar and accelerometers) has demonstrated older adults have extremely low mobility during hospitalization. Although these objective methods provide an unbiased way to monitor physical activity level and track in-hospital mobility change,^6-8 and have provided important information about mobility in the hospital, they are largely impractical in real-world settings.

While mobility technology appears to be advancing, there is a potential to assess in-hospital mobility using commonly administered and inexpensive tools. Many hospitals ask staff to regularly rate physical function (Braden and Morse score) as part of their standard-of-care procedures. The rating scales used have the potential to provide valuable information about mobility variations without using special equipment or burdening patients. The Braden Scale for Predicting Pressure Sore Risk is a good example of a validated assessment instrument that is better than nurses’ judgment, which is often confounded by nursing experience.⁹ This scale, which has 6 subscales (Sensory Perception, Moisture, Activity, Mobility, Nutrition, Friction and Shear), has shown high sensitivity in detecting patient condition changes in the clinical setting.¹⁰ The scale typically is used holistically to evaluate pressure ulcer risk, but the Activity subscale, which assesses mobility, could serve as a useful tool for predicting posthospital recovery and identifying needs for posthospital mobility interventions.

We conducted a study to evaluate the prognostic value of using the Braden Activity subscale (BAS) to identify in-hospital incident mobility impairment and recovery for predicting mortality and discharge status among hospitalized older adults.

The University of Florida Gainesville Health Science Center Institutional Review Board reviewed and approved the study protocol as exempt from human subjects’ research.

Design and Setting

The design followed a retrospective cohort study in which hospitalized patients were evaluated at admission (baseline) and assessed throughout their stay for incident mobility impairment and recovery. Data were collected in older adults (≥65 years old) hospitalized at UF Health Shands Hospital (University of Florida), an 852-bed level I trauma center in Gainesville, Florida.

Data Sources

Patient data from electronic medical records were warehoused in an integrated data repository (IDR) between January 1, 2009 and April 20, 2014. The IDR aggregates clinical and administrative system data, which can subsequently be used for research. The data were compiled in a de-identified longitudinal dataset that included demographics, Charlson Comorbidity Index,¹¹ hospital length of stay, BAS scores (at admission, during hospitalization, at discharge), discharge disposition (including in-hospital death), and mortality after hospitalization (from the national Social Security Death Index).

Patients

The study population consisted of 19,769 older adults (≥65 years old) hospitalized between January 1, 2009 and April 20, 2014.

Outcomes

The major outcomes were patients’ primary discharge disposition and posthospital mortality over 4.5-year follow-up. Discharge dispositions were divided into 9 categories: expired in hospital, other hospital admission, home, home care, hospice, rehabilitation, skilled nursing home, healthcare facility, or other, which included psychiatric facilities, court, or law enforcement.

Predictors

The BAS was used to identify incident mobility impairment and incident mobility recovery during hospitalization and subsequently was used to predict discharge disposition and mortality. The Braden scale,¹² which is commonly administered to predict pressure sores, has 6 subscales: Sensory Perception, Moisture, Activity, Mobility, Nutrition, and Friction and Shear. Each subscale has a score of 1 to 4, with higher scores representing higher activity levels. In particular, the BAS measures the mobility (walking and transferring) level of the hospitalized patient with a score of 1 (“patient is confined to bed”), 2 (“severely limited or nonexistent ability to walk; patient cannot bear his own weight and/or must be assisted into chair or wheelchair”), 3 (“patient walks occasionally during the day, but for very short distances, with or without assistance; he spends majority of each shift in bed or chair”), or 4 (“patient walks outside the room at least twice a day and inside the room at least once every 2 hours during waking hours”). The BAS is correlated with the total Braden scale¹⁰ and has shown excellent interrater reliability (interclass correlation coefficient, 0.96) among hospital staff.¹³ Analysis of the current dataset revealed excellent rater agreement across 3 working shifts (κ = 0.76 for first day of hospitalization in those hospitalized <3 days; κ = 0.70 for first day in those hospitalized ≥3 days).

UF Health Shands Hospital nursing staff administered the BAS at each shift change during a hospital stay (~3 times/d). Mobility scores were averaged across an entire day to reduce potential interrater variation. A daily average BAS score cutpoint was chosen to capture an absorbing mobility state. Average BAS score ≥3 was selected, as it indicates a patient is mobile most of the day, whereas average BAS score <3 indicates significant mobility impairment most of the day. The average daily score was calculated with a minimum of 3 determinations per day. Incident mobility impairment was defined as first transition from “being able to walk occasionally or twice a day outside or at least once every 2 hours during waking hours” to “severely limited or nonexistent ability to walk or confined to bed.” Numerically speaking, daily average BAS score transition from ≥3 at admission to <3 during hospitalization constituted a mobility impairment event. Incident mobility recovery was evaluated in those patient hospital observations that were “severely limited or nonexistent ability to walk or confined to bed” at admission. Incident mobility recovery was defined as first transition to “ability to walk occasionally or twice a day outside or at least once every 2 hours during waking hours.” A mobility recovery event was operationally defined as daily average BAS score transition from <3 at admission to daily average of ≥3 during hospitalization.

Data Analysis

Patient baseline characteristics are reported as counts, means, or medians. Chi-square statistics were used to test group differences for categorical variables, and analysis of variance was performed for continuous variables. Posthospital outcomes were evaluated descriptively and with time-to-event analyses. Kaplan-Meier curves and Wilcoxon P were also used to compare the survival probability for the mobility impairment and recovery groups. Although Cox proportional hazard regression is appropriate for these data, we found the proportionality assumption tenuous. As an alternative, logistic regression was used to model the probability of impairment/recovery outcomes. In addition, a survival time estimate that is robust to the proportionality assumption was derived according to Royston and Parmar^14,15 and Zhao et al.¹⁶ This approach reports the difference between 2 survival curves using the restricted mean—a measure of average survival using the area under the survival curve from time point zero to last observed follow-up time. All models were adjusted for age, sex, race, and hospital length of stay. Analyses were performed with R 3.1.1.¹⁷ All analyses were 2-tailed, and an α of 0.05 was considered statistically significant.

Table 1 lists the baseline characteristics of the hospitalized patients: 10,717 (54%) with normal mobility at admission and 9052 (46%) admitted with impaired mobility. Compared with patients admitted with normal mobility, those with impaired mobility at admission were older, mean (SD) 75.73 (7.84) years versus 73.73 (7.00) years; spent more days in the hospital, median 5 days versus 3 days; and had a higher Charlson Comorbidity Index, mean (SD) 2.59 (2.34) versus 2.22 (2.31). Patients with impaired mobility at admission had a significantly higher prevalence of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, and diabetes. However, cancer was significantly more prevalent among patients admitted with normal mobility compared with those admitted with impaired mobility.

Of the 10,717 patients with normal mobility at admission, 2218 (20.7%) had incident mobility impairment over a median follow-up of 3 days (interquartile range, 2-5 days). Of the 9052 patients admitted with impaired mobility, 4734 (52.3%) recovered from their impairment over a median follow-up of 5 days (interquartile range, 3-9 days).

In this study, we evaluated the predictive value of the BAS in assessing incident mobility impairment and recovery during hospitalization among older adults. Patients admitted with impaired mobility were older, spent more days in the hospital, and had more comorbidities than those admitted with normal mobility. Compared with older adults who did not develop incident mobility impairment during hospitalization, those who became mobility impaired had a higher posthospital mortality risk and a higher prevalence of in-hospital death and hospice discharge. In addition, compared with older adults who did not recover mobility in the hospital, those who recovered mobility had a lower posthospital mortality risk and a higher prevalence of home discharge. It is interesting that incident in the hospital appears to have a finite effect. The association was largely erased 6 months after discharge. This was also observed in patients who recovered their mobility in the hospital, but to a lesser extent. Overall, the results suggest that developing mobility impairment or recovering from mobility impairment in the hospital is an important predictor of discharge status and posthospital mortality.

The large number of patient observations and repeated evaluation of in-hospital mobility made this analysis possible. To our knowledge, this is the first large-scale study to evaluate the predictive value of the BAS in assessing mobility impairment and recovery during hospitalization among older adults. Such a test provides a simple and efficient assessment of in-hospital mobility changes that are sensitive to discharge locations and posthospital mortality risk.

Poor mobility in the hospital is associated with higher posthospital mortality. Kasotakis et al.¹⁸ evaluated the predictive value of a nursing staff–assessed clinical mobility score for surgical critically ill patients whose functional mobility was unimpaired on presentation. The Surgical Intensive Care Unit Optimal Mobility Score has been shown to be a reliable and valid tool for predicting mortality in a relatively young population (average age, 60 years). Using accelerometer technology with older adults, Ostir et al.⁷ found that each 100-step increase was associated with 2% and 3% lower risk of death over 2 years in the first and last 24 hours of hospitalization, respectively. The present mortality results show that mobility patterns in the hospital are crucially important for patients’ health the first 6 months after discharge. This finding suggests that developing mobility impairment in the hospital is a sign for significant and rapid health decline. It also suggests that interventions need to be started relatively early in order to reduce the risk of death. In contrast, patients who recover mobility in the hospital obtain a substantial mortality risk reduction. In-hospital interventions to enhance mobility recovery and prevent mobility impairment could have a large impact on posthospital adverse events, particularly for older patients, who are susceptible to disease complications.

Regarding discharge disposition, Sommerfeld and von Arbin¹⁹ found that the ability to rise from a chair (a component of mobility) during hospitalization was a strong predictor of early discharge home. Similarly, Vochteloo et al.²⁰ found that limited mobility as assessed with a questionnaire was associated with discharge to a location other than home among patients with hip fracture. We utilized existing information, collected at a relatively high resolution (3 times per day) that is often readily available without added patient burden. This is particularly important in the hospital setting, where added assessments in frail older adults and in those with multimorbid conditions is challenging. Although our approach is appealing, we should note that BAS scores were modified to reduce interrater variation and capture more absorbing mobility states over a hospitalized day, and that a similar approach would be required to replicate these results and provide clinical value to the BAS as a prognostic indicator of posthospital mortality.

Despite the strengths of this study, it had notable limitations. Pooling BAS scores could have modified the interpretation and clinical implications of the results. Although we had a large number of patient observations, this retrospective analysis may have had biases that were not completely considered. In addition, the results of this single-center study cannot be generalized across all hospital systems. The Braden activity sub score has demonstrated good validity and reliability for activity changes¹³, but this measure was not objectively ascertained as demonstrated by others using accelerometers^6-7. Moreover, the medical records used did not provide prehospital patient mobility status, limiting adjustments for prehospital mobility function. Despite these limitations, this study represents an important initial step in validating a simple and efficient clinical tool for identifying in-hospital mobility impairment and recovery and predicting posthospital adverse outcomes.

BAS assessment of incident mobility impairment and recovery in the hospital setting has prognostic value in predicting discharge disposition, in-hospital death, and posthospital mortality risk. That the majority of the effect appears to occur within the first 6 months after discharge suggests that interventions to improve mobility should be started during hospitalization or expeditiously after discharge. Overall, this study’s results showed that a simple and efficient mobility status assessment can become a valuable clinical and administrative tool for targeting and improving mobility in the hospital and after discharge in older adults.

Acknowledgments

This work was supported by the National Institutes of Health and the National Center for Advancing Translational Sciences (NIH/NCATS) Clinical and Translational Science Award to the University of Florida (UL1 TR000064) and by the University of Florida’s Claude D. Pepper Center (P30AG028740-R6, significant contributions from the Data and Applied Science Core and Biostatistical Core).

Disclosure

Nothing to report.

In-hospital mobility (walking and transferring) is an important modifiable factor for posthospital functional outcomes and mortality among older adults.^1-4 In fact, daily mobility assessment has been considered for a standard clinical evaluation of the hospitalized older adult.^5,6 This would provide a ready source for targeting patients at risk for mobility impairment and identifying strategies to prevent in-hospital mobility limitation and posthospital functional decline. Despite their potential importance, mobility assessment tools have not been readily adopted in the hospital setting.

There are various ways to assess mobility in hospital settings. Mobility tracking technology (radar and accelerometers) has demonstrated older adults have extremely low mobility during hospitalization. Although these objective methods provide an unbiased way to monitor physical activity level and track in-hospital mobility change,^6-8 and have provided important information about mobility in the hospital, they are largely impractical in real-world settings.

While mobility technology appears to be advancing, there is a potential to assess in-hospital mobility using commonly administered and inexpensive tools. Many hospitals ask staff to regularly rate physical function (Braden and Morse score) as part of their standard-of-care procedures. The rating scales used have the potential to provide valuable information about mobility variations without using special equipment or burdening patients. The Braden Scale for Predicting Pressure Sore Risk is a good example of a validated assessment instrument that is better than nurses’ judgment, which is often confounded by nursing experience.⁹ This scale, which has 6 subscales (Sensory Perception, Moisture, Activity, Mobility, Nutrition, Friction and Shear), has shown high sensitivity in detecting patient condition changes in the clinical setting.¹⁰ The scale typically is used holistically to evaluate pressure ulcer risk, but the Activity subscale, which assesses mobility, could serve as a useful tool for predicting posthospital recovery and identifying needs for posthospital mobility interventions.

We conducted a study to evaluate the prognostic value of using the Braden Activity subscale (BAS) to identify in-hospital incident mobility impairment and recovery for predicting mortality and discharge status among hospitalized older adults.

The University of Florida Gainesville Health Science Center Institutional Review Board reviewed and approved the study protocol as exempt from human subjects’ research.

Design and Setting

The design followed a retrospective cohort study in which hospitalized patients were evaluated at admission (baseline) and assessed throughout their stay for incident mobility impairment and recovery. Data were collected in older adults (≥65 years old) hospitalized at UF Health Shands Hospital (University of Florida), an 852-bed level I trauma center in Gainesville, Florida.

Data Sources

Patient data from electronic medical records were warehoused in an integrated data repository (IDR) between January 1, 2009 and April 20, 2014. The IDR aggregates clinical and administrative system data, which can subsequently be used for research. The data were compiled in a de-identified longitudinal dataset that included demographics, Charlson Comorbidity Index,¹¹ hospital length of stay, BAS scores (at admission, during hospitalization, at discharge), discharge disposition (including in-hospital death), and mortality after hospitalization (from the national Social Security Death Index).

Patients

The study population consisted of 19,769 older adults (≥65 years old) hospitalized between January 1, 2009 and April 20, 2014.

Outcomes

The major outcomes were patients’ primary discharge disposition and posthospital mortality over 4.5-year follow-up. Discharge dispositions were divided into 9 categories: expired in hospital, other hospital admission, home, home care, hospice, rehabilitation, skilled nursing home, healthcare facility, or other, which included psychiatric facilities, court, or law enforcement.

Predictors

The BAS was used to identify incident mobility impairment and incident mobility recovery during hospitalization and subsequently was used to predict discharge disposition and mortality. The Braden scale,¹² which is commonly administered to predict pressure sores, has 6 subscales: Sensory Perception, Moisture, Activity, Mobility, Nutrition, and Friction and Shear. Each subscale has a score of 1 to 4, with higher scores representing higher activity levels. In particular, the BAS measures the mobility (walking and transferring) level of the hospitalized patient with a score of 1 (“patient is confined to bed”), 2 (“severely limited or nonexistent ability to walk; patient cannot bear his own weight and/or must be assisted into chair or wheelchair”), 3 (“patient walks occasionally during the day, but for very short distances, with or without assistance; he spends majority of each shift in bed or chair”), or 4 (“patient walks outside the room at least twice a day and inside the room at least once every 2 hours during waking hours”). The BAS is correlated with the total Braden scale¹⁰ and has shown excellent interrater reliability (interclass correlation coefficient, 0.96) among hospital staff.¹³ Analysis of the current dataset revealed excellent rater agreement across 3 working shifts (κ = 0.76 for first day of hospitalization in those hospitalized <3 days; κ = 0.70 for first day in those hospitalized ≥3 days).

UF Health Shands Hospital nursing staff administered the BAS at each shift change during a hospital stay (~3 times/d). Mobility scores were averaged across an entire day to reduce potential interrater variation. A daily average BAS score cutpoint was chosen to capture an absorbing mobility state. Average BAS score ≥3 was selected, as it indicates a patient is mobile most of the day, whereas average BAS score <3 indicates significant mobility impairment most of the day. The average daily score was calculated with a minimum of 3 determinations per day. Incident mobility impairment was defined as first transition from “being able to walk occasionally or twice a day outside or at least once every 2 hours during waking hours” to “severely limited or nonexistent ability to walk or confined to bed.” Numerically speaking, daily average BAS score transition from ≥3 at admission to <3 during hospitalization constituted a mobility impairment event. Incident mobility recovery was evaluated in those patient hospital observations that were “severely limited or nonexistent ability to walk or confined to bed” at admission. Incident mobility recovery was defined as first transition to “ability to walk occasionally or twice a day outside or at least once every 2 hours during waking hours.” A mobility recovery event was operationally defined as daily average BAS score transition from <3 at admission to daily average of ≥3 during hospitalization.

Data Analysis

Patient baseline characteristics are reported as counts, means, or medians. Chi-square statistics were used to test group differences for categorical variables, and analysis of variance was performed for continuous variables. Posthospital outcomes were evaluated descriptively and with time-to-event analyses. Kaplan-Meier curves and Wilcoxon P were also used to compare the survival probability for the mobility impairment and recovery groups. Although Cox proportional hazard regression is appropriate for these data, we found the proportionality assumption tenuous. As an alternative, logistic regression was used to model the probability of impairment/recovery outcomes. In addition, a survival time estimate that is robust to the proportionality assumption was derived according to Royston and Parmar^14,15 and Zhao et al.¹⁶ This approach reports the difference between 2 survival curves using the restricted mean—a measure of average survival using the area under the survival curve from time point zero to last observed follow-up time. All models were adjusted for age, sex, race, and hospital length of stay. Analyses were performed with R 3.1.1.¹⁷ All analyses were 2-tailed, and an α of 0.05 was considered statistically significant.

Table 1 lists the baseline characteristics of the hospitalized patients: 10,717 (54%) with normal mobility at admission and 9052 (46%) admitted with impaired mobility. Compared with patients admitted with normal mobility, those with impaired mobility at admission were older, mean (SD) 75.73 (7.84) years versus 73.73 (7.00) years; spent more days in the hospital, median 5 days versus 3 days; and had a higher Charlson Comorbidity Index, mean (SD) 2.59 (2.34) versus 2.22 (2.31). Patients with impaired mobility at admission had a significantly higher prevalence of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, and diabetes. However, cancer was significantly more prevalent among patients admitted with normal mobility compared with those admitted with impaired mobility.

Of the 10,717 patients with normal mobility at admission, 2218 (20.7%) had incident mobility impairment over a median follow-up of 3 days (interquartile range, 2-5 days). Of the 9052 patients admitted with impaired mobility, 4734 (52.3%) recovered from their impairment over a median follow-up of 5 days (interquartile range, 3-9 days).

In this study, we evaluated the predictive value of the BAS in assessing incident mobility impairment and recovery during hospitalization among older adults. Patients admitted with impaired mobility were older, spent more days in the hospital, and had more comorbidities than those admitted with normal mobility. Compared with older adults who did not develop incident mobility impairment during hospitalization, those who became mobility impaired had a higher posthospital mortality risk and a higher prevalence of in-hospital death and hospice discharge. In addition, compared with older adults who did not recover mobility in the hospital, those who recovered mobility had a lower posthospital mortality risk and a higher prevalence of home discharge. It is interesting that incident in the hospital appears to have a finite effect. The association was largely erased 6 months after discharge. This was also observed in patients who recovered their mobility in the hospital, but to a lesser extent. Overall, the results suggest that developing mobility impairment or recovering from mobility impairment in the hospital is an important predictor of discharge status and posthospital mortality.

The large number of patient observations and repeated evaluation of in-hospital mobility made this analysis possible. To our knowledge, this is the first large-scale study to evaluate the predictive value of the BAS in assessing mobility impairment and recovery during hospitalization among older adults. Such a test provides a simple and efficient assessment of in-hospital mobility changes that are sensitive to discharge locations and posthospital mortality risk.

Poor mobility in the hospital is associated with higher posthospital mortality. Kasotakis et al.¹⁸ evaluated the predictive value of a nursing staff–assessed clinical mobility score for surgical critically ill patients whose functional mobility was unimpaired on presentation. The Surgical Intensive Care Unit Optimal Mobility Score has been shown to be a reliable and valid tool for predicting mortality in a relatively young population (average age, 60 years). Using accelerometer technology with older adults, Ostir et al.⁷ found that each 100-step increase was associated with 2% and 3% lower risk of death over 2 years in the first and last 24 hours of hospitalization, respectively. The present mortality results show that mobility patterns in the hospital are crucially important for patients’ health the first 6 months after discharge. This finding suggests that developing mobility impairment in the hospital is a sign for significant and rapid health decline. It also suggests that interventions need to be started relatively early in order to reduce the risk of death. In contrast, patients who recover mobility in the hospital obtain a substantial mortality risk reduction. In-hospital interventions to enhance mobility recovery and prevent mobility impairment could have a large impact on posthospital adverse events, particularly for older patients, who are susceptible to disease complications.

Regarding discharge disposition, Sommerfeld and von Arbin¹⁹ found that the ability to rise from a chair (a component of mobility) during hospitalization was a strong predictor of early discharge home. Similarly, Vochteloo et al.²⁰ found that limited mobility as assessed with a questionnaire was associated with discharge to a location other than home among patients with hip fracture. We utilized existing information, collected at a relatively high resolution (3 times per day) that is often readily available without added patient burden. This is particularly important in the hospital setting, where added assessments in frail older adults and in those with multimorbid conditions is challenging. Although our approach is appealing, we should note that BAS scores were modified to reduce interrater variation and capture more absorbing mobility states over a hospitalized day, and that a similar approach would be required to replicate these results and provide clinical value to the BAS as a prognostic indicator of posthospital mortality.

Despite the strengths of this study, it had notable limitations. Pooling BAS scores could have modified the interpretation and clinical implications of the results. Although we had a large number of patient observations, this retrospective analysis may have had biases that were not completely considered. In addition, the results of this single-center study cannot be generalized across all hospital systems. The Braden activity sub score has demonstrated good validity and reliability for activity changes¹³, but this measure was not objectively ascertained as demonstrated by others using accelerometers^6-7. Moreover, the medical records used did not provide prehospital patient mobility status, limiting adjustments for prehospital mobility function. Despite these limitations, this study represents an important initial step in validating a simple and efficient clinical tool for identifying in-hospital mobility impairment and recovery and predicting posthospital adverse outcomes.

BAS assessment of incident mobility impairment and recovery in the hospital setting has prognostic value in predicting discharge disposition, in-hospital death, and posthospital mortality risk. That the majority of the effect appears to occur within the first 6 months after discharge suggests that interventions to improve mobility should be started during hospitalization or expeditiously after discharge. Overall, this study’s results showed that a simple and efficient mobility status assessment can become a valuable clinical and administrative tool for targeting and improving mobility in the hospital and after discharge in older adults.

Acknowledgments

This work was supported by the National Institutes of Health and the National Center for Advancing Translational Sciences (NIH/NCATS) Clinical and Translational Science Award to the University of Florida (UL1 TR000064) and by the University of Florida’s Claude D. Pepper Center (P30AG028740-R6, significant contributions from the Data and Applied Science Core and Biostatistical Core).

Disclosure

Nothing to report.

In-hospital mobility (walking and transferring) is an important modifiable factor for posthospital functional outcomes and mortality among older adults.^1-4 In fact, daily mobility assessment has been considered for a standard clinical evaluation of the hospitalized older adult.^5,6 This would provide a ready source for targeting patients at risk for mobility impairment and identifying strategies to prevent in-hospital mobility limitation and posthospital functional decline. Despite their potential importance, mobility assessment tools have not been readily adopted in the hospital setting.

There are various ways to assess mobility in hospital settings. Mobility tracking technology (radar and accelerometers) has demonstrated older adults have extremely low mobility during hospitalization. Although these objective methods provide an unbiased way to monitor physical activity level and track in-hospital mobility change,^6-8 and have provided important information about mobility in the hospital, they are largely impractical in real-world settings.

While mobility technology appears to be advancing, there is a potential to assess in-hospital mobility using commonly administered and inexpensive tools. Many hospitals ask staff to regularly rate physical function (Braden and Morse score) as part of their standard-of-care procedures. The rating scales used have the potential to provide valuable information about mobility variations without using special equipment or burdening patients. The Braden Scale for Predicting Pressure Sore Risk is a good example of a validated assessment instrument that is better than nurses’ judgment, which is often confounded by nursing experience.⁹ This scale, which has 6 subscales (Sensory Perception, Moisture, Activity, Mobility, Nutrition, Friction and Shear), has shown high sensitivity in detecting patient condition changes in the clinical setting.¹⁰ The scale typically is used holistically to evaluate pressure ulcer risk, but the Activity subscale, which assesses mobility, could serve as a useful tool for predicting posthospital recovery and identifying needs for posthospital mobility interventions.

We conducted a study to evaluate the prognostic value of using the Braden Activity subscale (BAS) to identify in-hospital incident mobility impairment and recovery for predicting mortality and discharge status among hospitalized older adults.

The University of Florida Gainesville Health Science Center Institutional Review Board reviewed and approved the study protocol as exempt from human subjects’ research.

Design and Setting

The design followed a retrospective cohort study in which hospitalized patients were evaluated at admission (baseline) and assessed throughout their stay for incident mobility impairment and recovery. Data were collected in older adults (≥65 years old) hospitalized at UF Health Shands Hospital (University of Florida), an 852-bed level I trauma center in Gainesville, Florida.

Data Sources

Patient data from electronic medical records were warehoused in an integrated data repository (IDR) between January 1, 2009 and April 20, 2014. The IDR aggregates clinical and administrative system data, which can subsequently be used for research. The data were compiled in a de-identified longitudinal dataset that included demographics, Charlson Comorbidity Index,¹¹ hospital length of stay, BAS scores (at admission, during hospitalization, at discharge), discharge disposition (including in-hospital death), and mortality after hospitalization (from the national Social Security Death Index).

Patients

The study population consisted of 19,769 older adults (≥65 years old) hospitalized between January 1, 2009 and April 20, 2014.

Outcomes

The major outcomes were patients’ primary discharge disposition and posthospital mortality over 4.5-year follow-up. Discharge dispositions were divided into 9 categories: expired in hospital, other hospital admission, home, home care, hospice, rehabilitation, skilled nursing home, healthcare facility, or other, which included psychiatric facilities, court, or law enforcement.

Predictors

The BAS was used to identify incident mobility impairment and incident mobility recovery during hospitalization and subsequently was used to predict discharge disposition and mortality. The Braden scale,¹² which is commonly administered to predict pressure sores, has 6 subscales: Sensory Perception, Moisture, Activity, Mobility, Nutrition, and Friction and Shear. Each subscale has a score of 1 to 4, with higher scores representing higher activity levels. In particular, the BAS measures the mobility (walking and transferring) level of the hospitalized patient with a score of 1 (“patient is confined to bed”), 2 (“severely limited or nonexistent ability to walk; patient cannot bear his own weight and/or must be assisted into chair or wheelchair”), 3 (“patient walks occasionally during the day, but for very short distances, with or without assistance; he spends majority of each shift in bed or chair”), or 4 (“patient walks outside the room at least twice a day and inside the room at least once every 2 hours during waking hours”). The BAS is correlated with the total Braden scale¹⁰ and has shown excellent interrater reliability (interclass correlation coefficient, 0.96) among hospital staff.¹³ Analysis of the current dataset revealed excellent rater agreement across 3 working shifts (κ = 0.76 for first day of hospitalization in those hospitalized <3 days; κ = 0.70 for first day in those hospitalized ≥3 days).

UF Health Shands Hospital nursing staff administered the BAS at each shift change during a hospital stay (~3 times/d). Mobility scores were averaged across an entire day to reduce potential interrater variation. A daily average BAS score cutpoint was chosen to capture an absorbing mobility state. Average BAS score ≥3 was selected, as it indicates a patient is mobile most of the day, whereas average BAS score <3 indicates significant mobility impairment most of the day. The average daily score was calculated with a minimum of 3 determinations per day. Incident mobility impairment was defined as first transition from “being able to walk occasionally or twice a day outside or at least once every 2 hours during waking hours” to “severely limited or nonexistent ability to walk or confined to bed.” Numerically speaking, daily average BAS score transition from ≥3 at admission to <3 during hospitalization constituted a mobility impairment event. Incident mobility recovery was evaluated in those patient hospital observations that were “severely limited or nonexistent ability to walk or confined to bed” at admission. Incident mobility recovery was defined as first transition to “ability to walk occasionally or twice a day outside or at least once every 2 hours during waking hours.” A mobility recovery event was operationally defined as daily average BAS score transition from <3 at admission to daily average of ≥3 during hospitalization.

Data Analysis

Patient baseline characteristics are reported as counts, means, or medians. Chi-square statistics were used to test group differences for categorical variables, and analysis of variance was performed for continuous variables. Posthospital outcomes were evaluated descriptively and with time-to-event analyses. Kaplan-Meier curves and Wilcoxon P were also used to compare the survival probability for the mobility impairment and recovery groups. Although Cox proportional hazard regression is appropriate for these data, we found the proportionality assumption tenuous. As an alternative, logistic regression was used to model the probability of impairment/recovery outcomes. In addition, a survival time estimate that is robust to the proportionality assumption was derived according to Royston and Parmar^14,15 and Zhao et al.¹⁶ This approach reports the difference between 2 survival curves using the restricted mean—a measure of average survival using the area under the survival curve from time point zero to last observed follow-up time. All models were adjusted for age, sex, race, and hospital length of stay. Analyses were performed with R 3.1.1.¹⁷ All analyses were 2-tailed, and an α of 0.05 was considered statistically significant.

Table 1 lists the baseline characteristics of the hospitalized patients: 10,717 (54%) with normal mobility at admission and 9052 (46%) admitted with impaired mobility. Compared with patients admitted with normal mobility, those with impaired mobility at admission were older, mean (SD) 75.73 (7.84) years versus 73.73 (7.00) years; spent more days in the hospital, median 5 days versus 3 days; and had a higher Charlson Comorbidity Index, mean (SD) 2.59 (2.34) versus 2.22 (2.31). Patients with impaired mobility at admission had a significantly higher prevalence of myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, and diabetes. However, cancer was significantly more prevalent among patients admitted with normal mobility compared with those admitted with impaired mobility.

Of the 10,717 patients with normal mobility at admission, 2218 (20.7%) had incident mobility impairment over a median follow-up of 3 days (interquartile range, 2-5 days). Of the 9052 patients admitted with impaired mobility, 4734 (52.3%) recovered from their impairment over a median follow-up of 5 days (interquartile range, 3-9 days).

In this study, we evaluated the predictive value of the BAS in assessing incident mobility impairment and recovery during hospitalization among older adults. Patients admitted with impaired mobility were older, spent more days in the hospital, and had more comorbidities than those admitted with normal mobility. Compared with older adults who did not develop incident mobility impairment during hospitalization, those who became mobility impaired had a higher posthospital mortality risk and a higher prevalence of in-hospital death and hospice discharge. In addition, compared with older adults who did not recover mobility in the hospital, those who recovered mobility had a lower posthospital mortality risk and a higher prevalence of home discharge. It is interesting that incident in the hospital appears to have a finite effect. The association was largely erased 6 months after discharge. This was also observed in patients who recovered their mobility in the hospital, but to a lesser extent. Overall, the results suggest that developing mobility impairment or recovering from mobility impairment in the hospital is an important predictor of discharge status and posthospital mortality.

The large number of patient observations and repeated evaluation of in-hospital mobility made this analysis possible. To our knowledge, this is the first large-scale study to evaluate the predictive value of the BAS in assessing mobility impairment and recovery during hospitalization among older adults. Such a test provides a simple and efficient assessment of in-hospital mobility changes that are sensitive to discharge locations and posthospital mortality risk.

Poor mobility in the hospital is associated with higher posthospital mortality. Kasotakis et al.¹⁸ evaluated the predictive value of a nursing staff–assessed clinical mobility score for surgical critically ill patients whose functional mobility was unimpaired on presentation. The Surgical Intensive Care Unit Optimal Mobility Score has been shown to be a reliable and valid tool for predicting mortality in a relatively young population (average age, 60 years). Using accelerometer technology with older adults, Ostir et al.⁷ found that each 100-step increase was associated with 2% and 3% lower risk of death over 2 years in the first and last 24 hours of hospitalization, respectively. The present mortality results show that mobility patterns in the hospital are crucially important for patients’ health the first 6 months after discharge. This finding suggests that developing mobility impairment in the hospital is a sign for significant and rapid health decline. It also suggests that interventions need to be started relatively early in order to reduce the risk of death. In contrast, patients who recover mobility in the hospital obtain a substantial mortality risk reduction. In-hospital interventions to enhance mobility recovery and prevent mobility impairment could have a large impact on posthospital adverse events, particularly for older patients, who are susceptible to disease complications.

Regarding discharge disposition, Sommerfeld and von Arbin¹⁹ found that the ability to rise from a chair (a component of mobility) during hospitalization was a strong predictor of early discharge home. Similarly, Vochteloo et al.²⁰ found that limited mobility as assessed with a questionnaire was associated with discharge to a location other than home among patients with hip fracture. We utilized existing information, collected at a relatively high resolution (3 times per day) that is often readily available without added patient burden. This is particularly important in the hospital setting, where added assessments in frail older adults and in those with multimorbid conditions is challenging. Although our approach is appealing, we should note that BAS scores were modified to reduce interrater variation and capture more absorbing mobility states over a hospitalized day, and that a similar approach would be required to replicate these results and provide clinical value to the BAS as a prognostic indicator of posthospital mortality.

Despite the strengths of this study, it had notable limitations. Pooling BAS scores could have modified the interpretation and clinical implications of the results. Although we had a large number of patient observations, this retrospective analysis may have had biases that were not completely considered. In addition, the results of this single-center study cannot be generalized across all hospital systems. The Braden activity sub score has demonstrated good validity and reliability for activity changes¹³, but this measure was not objectively ascertained as demonstrated by others using accelerometers^6-7. Moreover, the medical records used did not provide prehospital patient mobility status, limiting adjustments for prehospital mobility function. Despite these limitations, this study represents an important initial step in validating a simple and efficient clinical tool for identifying in-hospital mobility impairment and recovery and predicting posthospital adverse outcomes.

BAS assessment of incident mobility impairment and recovery in the hospital setting has prognostic value in predicting discharge disposition, in-hospital death, and posthospital mortality risk. That the majority of the effect appears to occur within the first 6 months after discharge suggests that interventions to improve mobility should be started during hospitalization or expeditiously after discharge. Overall, this study’s results showed that a simple and efficient mobility status assessment can become a valuable clinical and administrative tool for targeting and improving mobility in the hospital and after discharge in older adults.

Acknowledgments

This work was supported by the National Institutes of Health and the National Center for Advancing Translational Sciences (NIH/NCATS) Clinical and Translational Science Award to the University of Florida (UL1 TR000064) and by the University of Florida’s Claude D. Pepper Center (P30AG028740-R6, significant contributions from the Data and Applied Science Core and Biostatistical Core).

Disclosure

Nothing to report.

Autosomal dominant polycystic kidney disease (ADPKD) has significant extrarenal manifestations. Hypertension is a common complication, arises early in the course of the disease, and is implicated in the development of left ventricular hypertrophy. Patients with ADPKD are also at risk of other cardiovascular complications (Table 1).

This article reviews the timely diagnosis of these common ADPKD complications and how to manage them.

ADPKD ACCOUNTS FOR 10% OF END-STAGE RENAL DISEASE

ADPKD is a genetic condition characterized by multiple renal cysts.¹ Progressive enlargement of these cysts leads to a gradual decline in kidney function and eventually end-stage renal disease by the fifth or sixth decade of life.² Worldwide, about 12.5 million people have ADPKD, and it accounts for about 10% of cases of end-stage renal disease.^1,3,4

ADPKD has a variety of clinical presentations, including (in decreasing order of frequency) hypertension, flank pain, abdominal masses, urinary tract infection, renal failure, renal stones, and cerebrovascular accidents.²

Extrarenal complications are common and include hepatic cysts, hypertension, left ventricular hypertrophy, valvular heart disease, intracranial and extracranial aneurysms, pancreatic cysts, and diverticulosis.^1–5

Less-common complications are dissection of the aorta and the internal carotid, vertebral, and iliac arteries^6–10; aneurysm of the coronary, popliteal, and splenic arteries^11–14; atrial myxoma¹⁵; cardiomyopathy¹⁶; pericardial effusion¹⁷; intracranial arterial dolichoectasia¹⁸; arachnoid cysts²; and intraoperative inferior vena cava syndrome (normally in ADPKD patients,  pressure on the inferior vena cava results in compensatory sympathetic overactivity to maintain blood pressure), which occurs due to reduced sympathetic output under the influence of epidural or general anesthesia.¹⁹

Cardiovascular complications, especially cardiac hypertrophy and coronary artery disease, are now the leading cause of death in patients with ADPKD, as renal replacement therapy has improved and made death from end-stage renal disease less common.^20,21

HYPERTENSION IN ADPKD

Hypertension is the most frequent initial presentation of ADPKD, occurring in 50% to 75% of cases and usually preceding the onset of renal failure.^2,22 Hypertension is more common in male ADPKD patients, begins early in the course of the disease, and is diagnosed around the fourth decade of life.²¹

In a study in 2007, de Almeida et al²³ used 24-hour ambulatory blood pressure monitoring early in the course of ADPKD and found significantly higher systolic, diastolic, and mean 24-hour blood pressures in ADPKD patients who had normal in-office blood pressure than in normotensive controls. In addition, nighttime systolic, nighttime diastolic, and nighttime mean blood pressures were significantly higher in the ADPKD group. 

Hypertension is strongly associated with an accelerated decline in renal function to end-stage renal disease, development of left ventricular hypertrophy, and cardiovascular death.^20,24

Although a prospective study²⁵ showed a strong association between renal stones and hypertension in ADPKD, the relation between them is not clear. The incidence of renal stones is higher in hypertensive than in normotensive ADPKD patients, although evidence has to be established whether nephro­lithiasis is a risk factor for hypertension or the other way around.²⁵

Hypertension in ADPKD is multifactorial (Figure 1). The major factors associated with its development are increased activation of the renin-angiotensin-aldosterone system (RAAS); overexpression of endothelin receptor subtype A (ET-A) in cystic kidneys; increased production of endothelin 1 (ET-1); and sodium retention.^26–31

The renin-angiotensin-aldosterone system

Activation of the RAAS plays a major role in the development and maintenance of hypertension in ADPKD. This is thought to be mainly due to progressive enlargement of renal cysts, which causes renal arteriolar attenuation and ischemia secondary to pressure effects, which in turn activates the RAAS.^{26,30,32–34} Two studies in patients with normal renal function found that cyst growth and increasing kidney volume have a strong relationship with the development of hypertension and declining kidney function.^35,36

Ectopic secretion of RAAS components in polycystic kidneys has also been implicated in the development of hypertension, whereby renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II receptors are produced in the epithelium of cysts and dilated tubules in polycystic kidneys.^37–39 Proximal renal cysts and tubules produce ectopic angiotensinogen, which is converted to angiotensin I by renin in distal renal cysts. Angiotensin I is converted to angiotensin II by ACE in distal tubules, which in turn stimulates angiotensin II receptors, causing sodium and water retention in distal tubules.³⁷ This may be responsible for hypertension in the initial stages; however, RAAS hyperactivity due to renal injury may predominate during later stages.³⁷

Increased RAAS activity also increases sympathetic output, which in turn raises catecholamine levels and blood pressure.³⁴ A study showed higher levels of plasma catecholamines in ADPKD hypertensive patients irrespective of renal function than in patients with essential hypertension.⁴⁰

ET-A receptor and ET-1

A few studies have shown that in ADPKD patients, increased density of ET-A receptors and overproduction of ET-1, a potent vasoconstrictor, play a significant role in the development of hypertension and gradual loss of kidney function due to cyst enlargement and interstitial scarring.^28,29 Ong et al²⁹ found that expression of ET-A receptors is increased in smooth muscle cells of renal arteries, glomerular mesangial cells, and cyst epithelia in ADPKD.

Studies in ADPKD patients with preserved renal function have linked high blood pressure to sodium retention and volume expansion.^30,31,41 However, this phenomenon reverses when there is significant renal impairment in ADPKD.

As evidence of this, a study demonstrated significantly more natriuresis in patients with renal failure due to ADPKD than in patients with a similar degree of renal failure due to chronic glomerulonephritis.³¹ Moreover, another study found that the prevalence of hypertension is higher in ADPKD patients than in those with other nephropathies with preserved renal function, but this association reverses with significant decline in kidney function.²²

MANAGING HYPERTENSION IN ADPKD

Early diagnosis of hypertension and effective control of it, even before ADPKD is diagnosed, is crucial to reduce cardiovascular mortality. Aggressive blood pressure control in the prehypertensive phase of ADPKD will also help reduce the incidence of left ventricular hypertrophy and mitral regurgitation and slow the progression of renal failure (Figure 2).

A meta-analysis⁴² revealed hypertension to be present in 20% of ADPKD patients younger than 21, and many of them were undiagnosed. This study also suggests that patients at risk of hypertension (ie, all patients with ADPKD)  should be routinely screened for it.

Ambulatory blood pressure monitoring may play an important role in diagnosing hypertension early in the prehypertensive stage of ADPKD.²³

Target blood pressures: No consensus

Two well-powered double-blind, placebo-controlled trials, known as HALT-PKD Study A and HALT-PKD Study B, tested the effects of 2 different blood pressure targets and of monotherapy with an ACE inhibitor vs combination therapy with an ACE inhibitor plus an angiotensin II receptor blocker (ARB) on renal function, total kidney volume, left ventricular mass index, and urinary albumin excretion in the early (estimated glomerular filtration rate [eGFR] > 60 mL/min) and late (eGFR 25–60 mL/min) stages of ADPKD, respectively.^43,44

HALT-PKD Study A⁴³ found that, in the early stages of ADPKD with preserved renal function, meticulous control of blood pressure (95–110/60–75 mm Hg) was strongly correlated with significant reductions in left ventricular mass index, albuminuria, and rate of total kidney volume growth without remarkable alteration in renal function compared with standard blood pressure control (120–130/70–80 mm Hg). However, no notable differences were observed between the ACE inhibitor and ACE inhibitor-plus-ARB groups.⁴³

Despite the evidence, universal consensus guidelines are lacking, and the available guidelines on hypertension management have different blood pressure goals in patients with chronic kidney disease.

The eighth Joint National Committee guideline of 2014 recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetic and nondiabetic chronic kidney disease.⁴⁵

The National Institute for Health and Care Excellence 2011 guideline recommends a blood pressure goal of less than 130/80 mm Hg in chronic kidney disease patients.⁴⁶

The European Society of Hypertension and European Society of Cardiology joint 2013 guideline recommends a systolic blood pressure goal of less than 140 mm Hg in diabetic and nondiabetic patients with chronic kidney disease.⁴⁷

The 2016 Kidney Health Australia-Caring for Australians With Renal Impairment guideline for diagnosis and management of ADPKD⁴⁸ recommends a lower blood pressure goal of 96–110/60–75 mm Hg in patients with an eGFR greater than 60 mL/min/1.73 m² who can tolerate it without side effects, which is based on the findings of HALT-PKD Study A.⁴³

Helal et al recommend that blood pressure be controlled to less than 130/80 mm Hg, until there is more evidence for a safe and effective target blood pressure goal in ADPKD patients.⁴⁹

We recommend a target blood pressure less than 110/75 mm Hg in hypertensive ADPKD patients with preserved renal function who can tolerate this level, and less than 130/80 mm Hg in ADPKD patients with stage 3 chronic kidney disease. These targets  can be achieved with ACE inhibitor or ARB monotherapy.^43,44 However, no studies have established the safest lower limit of target blood pressure in ADPKD.

ACE inhibitors, ARBs are mainstays

Mainstays of antihypertensive drug therapy in ADPKD are ACE inhibitors and ARBs.

HALT-PKD Study B⁴⁴ demonstrated that, in the late stages of ADPKD, target blood pressure control (110–130/70–80 mm Hg) can be attained with ACE inhibitor monotherapy or with an ACE inhibitor plus an ARB, but the latter produced no additive benefit.

Patch et al,⁵⁰ in a retrospective cohort study, showed that broadening the spectrum of antihypertensive therapy decreases mortality in ADPKD patients. Evaluating ADPKD patients from the UK General Practice Research Database between 1991 and 2008, they found a trend toward lower mortality rates as the number of antihypertensive drugs prescribed within 1 year increased. They also observed that the prescription of RAAS-blocking agents increased from 7% in 1991 to 46% in 2008.⁵⁰ 

However, a 3-year prospective randomized double-blind study compared the effects of the ACE inhibitor ramipril and the beta-blocker metoprolol in hypertensive ADPKD patients.⁵¹ The results showed that effective blood pressure control could be achieved in both groups with no significant differences in left ventricular mass index, albuminuria, or kidney function.⁵¹

Treatment strategies

Lifestyle modification is the initial approach to the management of hypertension before starting drug therapy. Lifestyle changes include dietary salt restriction to less than 6 g/day, weight reduction, regular exercise, increased fluid intake (up to 3 L/day or to satisfy thirst), smoking cessation, and avoidance of caffeine.^47–49

ACE inhibitors are first-line drugs in hypertensive ADPKD patients.

ARBs can also be considered, but there is no role for dual ACE inhibitor and ARB therapy.^43,48 A study found ACE inhibitors to be more cost-effective and to decrease mortality rates to a greater extent than ARBs.⁵²

Beta-blockers or calcium channel blockers should be considered instead if ACE inhibitors and ARBs are contraindicated,  or as add-on drugs if ACE inhibitors and ARBs fail to reduce blood pressure adequately.^48,49

Diuretics are third-line agents. Thiazides are preferred in ADPKD patients with normal renal function and loop diuretics in those with impaired renal function.⁴⁹

LEFT VENTRICULAR HYPERTROPHY IN ADPKD

Increased left ventricular mass is an indirect indicator of untreated hypertension, and it often goes unnoticed in patients with undiagnosed ADPKD. Left ventricular hypertrophy is associated with arrhythmias and heart failure, which contribute significantly to cardiovascular mortality and adverse renal outcomes.^20,24

A 5-year randomized clinical trial by Cadnapaphornchai et al³⁶ in ADPKD patients between 4 and 21 years of age showed strong correlations between hypertension, left ventricular mass index, and kidney volume and a negative correlation between left ventricular mass index and renal function.

Several factors are thought to contribute to left ventricular hypertrophy in ADPKD (Figure 1).

Hypertension. Two studies of 24-hour ambulatory blood pressure monitoring showed that nocturnal blood pressures decreased less in normotensive and hypertensive ADPKD patients than in normotensive and hypertensive controls.^23,53 This persistent elevation of nocturnal blood pressure may contribute to  the development and progression of left ventricular hypertrophy.

On the other hand, Valero et al⁵⁴ reported that the left ventricular mass index was strongly associated with ambulatory systolic blood pressure rather than elevated nocturnal blood pressure in ADPKD patients compared with healthy controls.

FGF23. High levels of fibroblast growth factor 23 (FGF23) have been shown to be strongly associated with left ventricular hypertrophy in ADPKD. Experimental studies have shown that FGF23 is directly involved in the pathogenesis of left ventricular hypertrophy through stimulation of the calcineurin-nuclear factor of activated T cells pathway.

Faul et al⁵⁵ induced cardiac hypertrophy in mice that were deficient in klotho (a transmembrane protein that increases FGF23 affinity for FGF receptors) by injecting FGF23 intravenously.

Yildiz et al⁵⁶ observed higher levels of FGF23 in hypertensive and normotensive ADPKD patients with normal renal function than in healthy controls. They also found a lower elasticity index in the large and small arteries in normotensive and hypertensive ADPKD patients, which accounts for vascular dysfunction. High FGF23 levels may be responsible for the left ventricular hypertrophy seen in normotensive ADPKD patients with preserved renal function.

Polymorphisms in the ACE gene have been implicated in the development of cardiac hypertrophy in ADPKD.

Wanic-Kossowska et al⁵⁷ studied the association between ACE gene polymorphisms and cardiovascular complications in ADPKD patients. They found a higher prevalence of the homozygous DD genotype among ADPKD patients with end-stage renal disease than in those in the early stages of chronic kidney disease in ADPKD. Also, the DD genotype has been shown to be more strongly associated with left ventricular hypertrophy and left ventricular dysfunction than other (II or ID) genotypes. These findings suggest that the DD genotype carries higher risk for the development of end-stage renal disease, left ventricular hypertrophy, and other cardiovascular complications.

Preventing and halting progression of left ventricular hypertrophy primarily involves effective blood pressure control, especially in the early stages of ADPKD (Figure 2).

A 7-year prospective randomized trial in ADPKD patients with established hypertension and left ventricular hypertrophy proved that aggressive (< 120/80 mm Hg) compared with standard blood pressure control (135–140/85–90 mm Hg) significantly reduces left ventricular mass index. ACE inhibitors were preferred over calcium channel blockers.⁵⁸

HALT-PKD Study A showed that a significant decrease in left ventricular mass index can be achieved by aggressive blood pressure control (95–110/60–75 mm Hg) with an ACE inhibitor alone or in combination with an ARB in the early stages of ADPKD with preserved renal function.⁴³

A 5-year randomized clinical trial in children with borderline hypertension treated with an ACE inhibitor for effective control of blood pressure showed no change in left ventricular mass index or renal function.^36,59

These results support starting ACE inhibitor therapy early in the disease process when blood pressure is still normal or borderline to prevent the progression of left ventricular hypertrophy or worsening kidney function.

Since FGF23 is directly involved in the causation of left ventricular hypertrophy, FGF receptors may be potential therapeutic targets to prevent left ventricular hypertrophy in ADPKD. An FGF receptor blocker was shown to decrease left ventricular hypertrophy in rats with chronic kidney disease without affecting blood pressure.⁵⁵

INTRACRANIAL ANEURYSM IN ADPKD

Intracranial aneurysm is the most dangerous complication of ADPKD. When an aneurysm ruptures, the mortality rate is 4% to 7%, and 50% of survivors are left with residual neurologic deficits.^5,60,61

In various studies, the prevalence of intracranial aneurysm in ADPKD ranged from 4% to 41.2%, compared with 1% in the general population.^5,62,63 On follow-up ranging from 18 months to about 10 years, the incidence of new intracranial aneurysm was 2.6% to 13.3% in patients with previously normal findings on magnetic resonance angiography and 25% in patients with a history of intracranial aneurysm.^62,64,65

The most common sites are the middle cerebral artery (45%), internal carotid artery (40.5%), and anterior communicating artery (35.1%).⁶⁶ (The numbers add up to more than 100% because some patients have aneurysms in more than 1 site.) The mean size of a ruptured aneurysm was 6 mm per a recent systematic review.⁶⁶ Intracranial aneurysms 6 mm or larger are at highest risk of rupture.⁶⁶

SCREENING FOR INTRACRANIAL ANEURYSM

Timely screening and intervention for intracranial aneurysm is crucial to prevent death from intracranial hemorrhage.

Currently, there are no standard guidelines for screening and follow-up of intracranial aneurysm in ADPKD patients. However, some recommendations are available from the ADPKD Kidney Disease Improving Global Outcomes Controversies Conference³ and Kidney Health Australia—Caring for Australasians With Renal Impairment ADPKD guidelines⁶⁷ (Figure 3).

Imaging tests

Magnetic resonance angiography (MRA) with gadolinium enhancement and computed tomographic angiography (CTA) are recommended for screening in ADPKD patients with normal renal function,⁶⁷ but time-of-flight MRA without gadolinium is the imaging test of choice because it is noninvasive and poses no risk of nephrotoxicity or contrast allergy.^3,68 Further, gadolinium should be avoided in patients whose eGFR is 30 mL/min/1.73 m² or less because of risk of nephrogenic systemic sclerosis and fibrosis.^67,68

The sensitivity of time-of-flight MRA screening for intracranial aneurysm varies depending on the size of aneurysm; 67% for those less than 3 mm, 79% for those 3 to 5 mm, and 95% for those larger than 5 mm.⁶⁹ The sensitivity of CTA screening is 95% for aneurysms larger than 7 mm and 53% for those measuring 2 mm.^70,71 The specificity of CTA screening was reported to be 98.9% overall.⁷¹

When to screen

Screening for intracranial aneurysm is recommended at the time of ADPKD diagnosis for all high-risk patients, ie, those who have a family history of intracranial hemorrhage or aneurysm in an affected first-degree relative.⁶⁷ It is also recommended for ADPKD patients with a history of sudden-onset severe headache or neurologic symptoms.⁶⁷ A third group for whom screening is recommended is ADPKD patients who have no family history of intracranial aneurysm or hemorrhage but who are at risk of poor outcome if an intracranial aneurysm ruptures (eg, those undergoing major elective surgery, with uncontrolled blood pressure, on anticoagulation, with a history of or current smoking, and airline pilots).⁶⁷

Patients found to have an intracranial aneurysm on screening should be referred to a neurosurgeon and should undergo repeat MRA or CTA imaging every 6 to 24 months.³ High-risk ADPKD patients with normal findings on initial screening should have repeat MRA or CTA screening in 5 to 10 years unless they suffer from sudden-onset severe headache or neurologic symptoms.^65,67

Both smoking and high blood pressure increase the risk of formation and growth of intracranial aneurysm. Hence, meticulous control of blood pressure and smoking cessation are recommended in ADPKD patients.^3,67

CARDIAC VALVULAR ABNORMALITIES IN ADPKD

Of the valvular abnormalities that complicate ADPKD, the more common ones are mitral valve prolapse and mitral and aortic regurgitation. The less common ones are tricuspid valve prolapse and tricuspid regurgitation.^72–74

The pathophysiology underlying these valvular abnormalities is unclear. However, defective collagen synthesis and myxomatous degeneration have been demonstrated in histopathologic examination of affected valvular tissue.⁷⁵ Also, ACE gene polymorphism, especially the DD genotype, has been shown to be associated with cardiac valvular calcifications and valvular insufficiency.⁵⁷

Lumiaho et al⁷² found a higher prevalence of mitral valve prolapse, mitral regurgitation, and left ventricular hypertrophy in patients with ADPKD type 1 (due to abnormalities in PDK1) than in unaffected family members and healthy controls. The investigators speculated that mitral regurgitation is caused by the high blood pressure observed in ADPKD type 1 patients, since hypertension causes left ventricular hypertrophy and left ventricular dilatation. The severity of renal failure was related to mitral regurgitation but not mitral valve prolapse.

Similarly, Gabow et al²⁴ showed that there is no significant relationship between mitral valve prolapse and progression of renal disease in ADPKD.

Interestingly, Fick et al²⁰ found that mitral valve prolapse has no significant effect on cardiovascular mortality.

Atherosclerosis sets in early in ADPKD, resulting in coronary artery disease and adverse cardiovascular outcomes.

Coronary flow velocity reserve is the ability of coronary arteries to dilate in response to myocardial oxygen demand. Atherosclerosis decreases this reserve in ADPKD patients, as shown in several studies.

Turkmen et al, in a series of studies,^76–78 found that ADPKD patients had significantly less coronary flow velocity reserve, thicker carotid intima media (a surrogate marker of atherosclerosis), and greater insulin resistance than healthy controls. These findings imply that atherosclerosis begins very early in the course of ADPKD and has remarkable effects on cardiovascular morbidity and mortality.⁷⁶

Aneurysm. Although the risk of extracranial aneurysm is higher with ADPKD, coronary artery aneurysm is uncommon. The pathogenesis of coronary aneurysm has been linked to abnormal expression of the proteins polycystin 1 and polycystin 2 in vascular smooth muscle.^11,79 The PKD1 and PKD2 genes encode polycystin 1 and 2, respectively, in ADPKD. These polycystins are also expressed in the liver, kidneys, and myocardium and are involved in the regulation of intracellular calcium, stretch-activated ion channels, and vascular smooth muscle cell proliferation and apoptosis.^11,16 Abnormally expressed polycystin in ADPKD therefore has an impact on arterial wall integrity, resulting in focal medial defects in the vasculature that eventually develop into micro- and macroaneurysms.¹¹

Hadimeri et al⁷⁹ found a higher prevalence of coronary aneurysm and ectasia in ADPKD patients than in controls. Most coronary aneurysms are smaller than 1 cm; however, a coronary aneurysm measuring 4 cm in diameter was found at autopsy of an ADPKD patient.¹¹

Spontaneous coronary artery dissection is very rare in the general population, but Bobrie et al reported a case of it in an ADPKD patient.⁹

ATRIAL MYXOMA, CARDIOMYOPATHY, AND PERICARDIAL EFFUSION IN ADPKD

Atrial myxoma in ADPKD patients has been described in 2 case reports.^15,80 However, the association of atrial myxoma with ADPKD is poorly understood and may be a coincidental finding.

Cardiomyopathy in ADPKD has been linked to abnormalities in the intracellular calcium pathway, although a clear picture of its involvement has yet to be established.

Paavola et al¹⁶ described the pathophysiology of ADPKD-associated cardiomyopathy in PKD2 mutant zebrafish lacking polycystin 2. These mutants showed decreased cardiac output and had atrioventricular blocks. The findings  were attributed to abnormal intracellular calcium cycling. These findings correlated well with the frequent finding of idiopathic dilated cardiomyopathy in ADPKD patients, especially with PKD2 mutations.¹⁶ Also, 2 cases of dilated cardiomyopathy in ADPKD have been reported and thought to be related to PKD2 mutations.^81,82

Pericardial effusion. Even though the exact pathophysiology of pericardial effusion in ADPKD is unknown, it has been theorized to be related to defects in connective tissue and extracellular matrix due to PKD1 and PKD2 mutations. These abnormalities increase the compliance and impair the recoil capacity of connective tissue, which results in unusual distention of the parietal pericardium. This abnormal distention of the parietal pericardium together with increased extracellular volume may lead to pericardial effusion.¹⁷

Qian et al¹⁷ found a higher prevalence of pericardial effusion in ADPKD patients. It was generally asymptomatic, and the cause was attributed to these connective tissue and extracellular matrix abnormalities.

EMERGING THERAPIES AND TESTS

Recent trials have investigated the effects of vasopressin receptor antagonists, specifically V2 receptor blockers in ADPKD and its complications.

Tolvaptan has been shown to slow the rate of increase in cyst size and total kidney volume.^83,84 Also, a correlation between kidney size and diastolic blood pressure has been observed in ADPKD patients.⁸⁵ Reducing cyst volume may reduce pressure effects and decrease renal ischemia, which in turn may reduce RAAS activation; however, the evidence to support this hypothesis is poor. A major clinical trial of tolvaptan in ADPKD patients showed no effect on blood pressure control, but the drug slowed the rate of increase in total kidney volume and fall in eGFR.⁸³

Endothelin receptor antagonists are also in the preliminary stage of development for use in ADPKD. The effects of acute blockade of the renal endothelial system with bosentan were  investigated in animal models by Hocher et al.²⁸ This study showed a greater reduction in mean arterial pressure after bosentan administration, resulting in significantly decreased GFR and renal blood flow. Nonetheless, the mean arterial pressure-lowering effect of bosentan was more marked than the reductions in GFR and renal blood flow.

Raina et al,⁸⁶ in a pilot cross-sectional analysis, showed that urinary excretion of ET-1 is increased in ADPKD patients, and may serve as a surrogate marker for ET-1 in renal tissue and a noninvasive marker of early kidney injury.

Autosomal dominant polycystic kidney disease (ADPKD) has significant extrarenal manifestations. Hypertension is a common complication, arises early in the course of the disease, and is implicated in the development of left ventricular hypertrophy. Patients with ADPKD are also at risk of other cardiovascular complications (Table 1).

This article reviews the timely diagnosis of these common ADPKD complications and how to manage them.

ADPKD ACCOUNTS FOR 10% OF END-STAGE RENAL DISEASE

ADPKD is a genetic condition characterized by multiple renal cysts.¹ Progressive enlargement of these cysts leads to a gradual decline in kidney function and eventually end-stage renal disease by the fifth or sixth decade of life.² Worldwide, about 12.5 million people have ADPKD, and it accounts for about 10% of cases of end-stage renal disease.^1,3,4

ADPKD has a variety of clinical presentations, including (in decreasing order of frequency) hypertension, flank pain, abdominal masses, urinary tract infection, renal failure, renal stones, and cerebrovascular accidents.²

Extrarenal complications are common and include hepatic cysts, hypertension, left ventricular hypertrophy, valvular heart disease, intracranial and extracranial aneurysms, pancreatic cysts, and diverticulosis.^1–5

Less-common complications are dissection of the aorta and the internal carotid, vertebral, and iliac arteries^6–10; aneurysm of the coronary, popliteal, and splenic arteries^11–14; atrial myxoma¹⁵; cardiomyopathy¹⁶; pericardial effusion¹⁷; intracranial arterial dolichoectasia¹⁸; arachnoid cysts²; and intraoperative inferior vena cava syndrome (normally in ADPKD patients,  pressure on the inferior vena cava results in compensatory sympathetic overactivity to maintain blood pressure), which occurs due to reduced sympathetic output under the influence of epidural or general anesthesia.¹⁹

Cardiovascular complications, especially cardiac hypertrophy and coronary artery disease, are now the leading cause of death in patients with ADPKD, as renal replacement therapy has improved and made death from end-stage renal disease less common.^20,21

HYPERTENSION IN ADPKD

Hypertension is the most frequent initial presentation of ADPKD, occurring in 50% to 75% of cases and usually preceding the onset of renal failure.^2,22 Hypertension is more common in male ADPKD patients, begins early in the course of the disease, and is diagnosed around the fourth decade of life.²¹

In a study in 2007, de Almeida et al²³ used 24-hour ambulatory blood pressure monitoring early in the course of ADPKD and found significantly higher systolic, diastolic, and mean 24-hour blood pressures in ADPKD patients who had normal in-office blood pressure than in normotensive controls. In addition, nighttime systolic, nighttime diastolic, and nighttime mean blood pressures were significantly higher in the ADPKD group. 

Hypertension is strongly associated with an accelerated decline in renal function to end-stage renal disease, development of left ventricular hypertrophy, and cardiovascular death.^20,24

Although a prospective study²⁵ showed a strong association between renal stones and hypertension in ADPKD, the relation between them is not clear. The incidence of renal stones is higher in hypertensive than in normotensive ADPKD patients, although evidence has to be established whether nephro­lithiasis is a risk factor for hypertension or the other way around.²⁵

Hypertension in ADPKD is multifactorial (Figure 1). The major factors associated with its development are increased activation of the renin-angiotensin-aldosterone system (RAAS); overexpression of endothelin receptor subtype A (ET-A) in cystic kidneys; increased production of endothelin 1 (ET-1); and sodium retention.^26–31

The renin-angiotensin-aldosterone system

Activation of the RAAS plays a major role in the development and maintenance of hypertension in ADPKD. This is thought to be mainly due to progressive enlargement of renal cysts, which causes renal arteriolar attenuation and ischemia secondary to pressure effects, which in turn activates the RAAS.^{26,30,32–34} Two studies in patients with normal renal function found that cyst growth and increasing kidney volume have a strong relationship with the development of hypertension and declining kidney function.^35,36

Ectopic secretion of RAAS components in polycystic kidneys has also been implicated in the development of hypertension, whereby renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II receptors are produced in the epithelium of cysts and dilated tubules in polycystic kidneys.^37–39 Proximal renal cysts and tubules produce ectopic angiotensinogen, which is converted to angiotensin I by renin in distal renal cysts. Angiotensin I is converted to angiotensin II by ACE in distal tubules, which in turn stimulates angiotensin II receptors, causing sodium and water retention in distal tubules.³⁷ This may be responsible for hypertension in the initial stages; however, RAAS hyperactivity due to renal injury may predominate during later stages.³⁷

Increased RAAS activity also increases sympathetic output, which in turn raises catecholamine levels and blood pressure.³⁴ A study showed higher levels of plasma catecholamines in ADPKD hypertensive patients irrespective of renal function than in patients with essential hypertension.⁴⁰

ET-A receptor and ET-1

A few studies have shown that in ADPKD patients, increased density of ET-A receptors and overproduction of ET-1, a potent vasoconstrictor, play a significant role in the development of hypertension and gradual loss of kidney function due to cyst enlargement and interstitial scarring.^28,29 Ong et al²⁹ found that expression of ET-A receptors is increased in smooth muscle cells of renal arteries, glomerular mesangial cells, and cyst epithelia in ADPKD.

Studies in ADPKD patients with preserved renal function have linked high blood pressure to sodium retention and volume expansion.^30,31,41 However, this phenomenon reverses when there is significant renal impairment in ADPKD.

As evidence of this, a study demonstrated significantly more natriuresis in patients with renal failure due to ADPKD than in patients with a similar degree of renal failure due to chronic glomerulonephritis.³¹ Moreover, another study found that the prevalence of hypertension is higher in ADPKD patients than in those with other nephropathies with preserved renal function, but this association reverses with significant decline in kidney function.²²

MANAGING HYPERTENSION IN ADPKD

Early diagnosis of hypertension and effective control of it, even before ADPKD is diagnosed, is crucial to reduce cardiovascular mortality. Aggressive blood pressure control in the prehypertensive phase of ADPKD will also help reduce the incidence of left ventricular hypertrophy and mitral regurgitation and slow the progression of renal failure (Figure 2).

A meta-analysis⁴² revealed hypertension to be present in 20% of ADPKD patients younger than 21, and many of them were undiagnosed. This study also suggests that patients at risk of hypertension (ie, all patients with ADPKD)  should be routinely screened for it.

Ambulatory blood pressure monitoring may play an important role in diagnosing hypertension early in the prehypertensive stage of ADPKD.²³

Target blood pressures: No consensus

Two well-powered double-blind, placebo-controlled trials, known as HALT-PKD Study A and HALT-PKD Study B, tested the effects of 2 different blood pressure targets and of monotherapy with an ACE inhibitor vs combination therapy with an ACE inhibitor plus an angiotensin II receptor blocker (ARB) on renal function, total kidney volume, left ventricular mass index, and urinary albumin excretion in the early (estimated glomerular filtration rate [eGFR] > 60 mL/min) and late (eGFR 25–60 mL/min) stages of ADPKD, respectively.^43,44

HALT-PKD Study A⁴³ found that, in the early stages of ADPKD with preserved renal function, meticulous control of blood pressure (95–110/60–75 mm Hg) was strongly correlated with significant reductions in left ventricular mass index, albuminuria, and rate of total kidney volume growth without remarkable alteration in renal function compared with standard blood pressure control (120–130/70–80 mm Hg). However, no notable differences were observed between the ACE inhibitor and ACE inhibitor-plus-ARB groups.⁴³

Despite the evidence, universal consensus guidelines are lacking, and the available guidelines on hypertension management have different blood pressure goals in patients with chronic kidney disease.

The eighth Joint National Committee guideline of 2014 recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetic and nondiabetic chronic kidney disease.⁴⁵

The National Institute for Health and Care Excellence 2011 guideline recommends a blood pressure goal of less than 130/80 mm Hg in chronic kidney disease patients.⁴⁶

The European Society of Hypertension and European Society of Cardiology joint 2013 guideline recommends a systolic blood pressure goal of less than 140 mm Hg in diabetic and nondiabetic patients with chronic kidney disease.⁴⁷

The 2016 Kidney Health Australia-Caring for Australians With Renal Impairment guideline for diagnosis and management of ADPKD⁴⁸ recommends a lower blood pressure goal of 96–110/60–75 mm Hg in patients with an eGFR greater than 60 mL/min/1.73 m² who can tolerate it without side effects, which is based on the findings of HALT-PKD Study A.⁴³

Helal et al recommend that blood pressure be controlled to less than 130/80 mm Hg, until there is more evidence for a safe and effective target blood pressure goal in ADPKD patients.⁴⁹

We recommend a target blood pressure less than 110/75 mm Hg in hypertensive ADPKD patients with preserved renal function who can tolerate this level, and less than 130/80 mm Hg in ADPKD patients with stage 3 chronic kidney disease. These targets  can be achieved with ACE inhibitor or ARB monotherapy.^43,44 However, no studies have established the safest lower limit of target blood pressure in ADPKD.

ACE inhibitors, ARBs are mainstays

Mainstays of antihypertensive drug therapy in ADPKD are ACE inhibitors and ARBs.

HALT-PKD Study B⁴⁴ demonstrated that, in the late stages of ADPKD, target blood pressure control (110–130/70–80 mm Hg) can be attained with ACE inhibitor monotherapy or with an ACE inhibitor plus an ARB, but the latter produced no additive benefit.

Patch et al,⁵⁰ in a retrospective cohort study, showed that broadening the spectrum of antihypertensive therapy decreases mortality in ADPKD patients. Evaluating ADPKD patients from the UK General Practice Research Database between 1991 and 2008, they found a trend toward lower mortality rates as the number of antihypertensive drugs prescribed within 1 year increased. They also observed that the prescription of RAAS-blocking agents increased from 7% in 1991 to 46% in 2008.⁵⁰ 

However, a 3-year prospective randomized double-blind study compared the effects of the ACE inhibitor ramipril and the beta-blocker metoprolol in hypertensive ADPKD patients.⁵¹ The results showed that effective blood pressure control could be achieved in both groups with no significant differences in left ventricular mass index, albuminuria, or kidney function.⁵¹

Treatment strategies

Lifestyle modification is the initial approach to the management of hypertension before starting drug therapy. Lifestyle changes include dietary salt restriction to less than 6 g/day, weight reduction, regular exercise, increased fluid intake (up to 3 L/day or to satisfy thirst), smoking cessation, and avoidance of caffeine.^47–49

ACE inhibitors are first-line drugs in hypertensive ADPKD patients.

ARBs can also be considered, but there is no role for dual ACE inhibitor and ARB therapy.^43,48 A study found ACE inhibitors to be more cost-effective and to decrease mortality rates to a greater extent than ARBs.⁵²

Beta-blockers or calcium channel blockers should be considered instead if ACE inhibitors and ARBs are contraindicated,  or as add-on drugs if ACE inhibitors and ARBs fail to reduce blood pressure adequately.^48,49

Diuretics are third-line agents. Thiazides are preferred in ADPKD patients with normal renal function and loop diuretics in those with impaired renal function.⁴⁹

LEFT VENTRICULAR HYPERTROPHY IN ADPKD

Increased left ventricular mass is an indirect indicator of untreated hypertension, and it often goes unnoticed in patients with undiagnosed ADPKD. Left ventricular hypertrophy is associated with arrhythmias and heart failure, which contribute significantly to cardiovascular mortality and adverse renal outcomes.^20,24

A 5-year randomized clinical trial by Cadnapaphornchai et al³⁶ in ADPKD patients between 4 and 21 years of age showed strong correlations between hypertension, left ventricular mass index, and kidney volume and a negative correlation between left ventricular mass index and renal function.

Several factors are thought to contribute to left ventricular hypertrophy in ADPKD (Figure 1).

Hypertension. Two studies of 24-hour ambulatory blood pressure monitoring showed that nocturnal blood pressures decreased less in normotensive and hypertensive ADPKD patients than in normotensive and hypertensive controls.^23,53 This persistent elevation of nocturnal blood pressure may contribute to  the development and progression of left ventricular hypertrophy.

On the other hand, Valero et al⁵⁴ reported that the left ventricular mass index was strongly associated with ambulatory systolic blood pressure rather than elevated nocturnal blood pressure in ADPKD patients compared with healthy controls.

FGF23. High levels of fibroblast growth factor 23 (FGF23) have been shown to be strongly associated with left ventricular hypertrophy in ADPKD. Experimental studies have shown that FGF23 is directly involved in the pathogenesis of left ventricular hypertrophy through stimulation of the calcineurin-nuclear factor of activated T cells pathway.

Faul et al⁵⁵ induced cardiac hypertrophy in mice that were deficient in klotho (a transmembrane protein that increases FGF23 affinity for FGF receptors) by injecting FGF23 intravenously.

Yildiz et al⁵⁶ observed higher levels of FGF23 in hypertensive and normotensive ADPKD patients with normal renal function than in healthy controls. They also found a lower elasticity index in the large and small arteries in normotensive and hypertensive ADPKD patients, which accounts for vascular dysfunction. High FGF23 levels may be responsible for the left ventricular hypertrophy seen in normotensive ADPKD patients with preserved renal function.

Polymorphisms in the ACE gene have been implicated in the development of cardiac hypertrophy in ADPKD.

Wanic-Kossowska et al⁵⁷ studied the association between ACE gene polymorphisms and cardiovascular complications in ADPKD patients. They found a higher prevalence of the homozygous DD genotype among ADPKD patients with end-stage renal disease than in those in the early stages of chronic kidney disease in ADPKD. Also, the DD genotype has been shown to be more strongly associated with left ventricular hypertrophy and left ventricular dysfunction than other (II or ID) genotypes. These findings suggest that the DD genotype carries higher risk for the development of end-stage renal disease, left ventricular hypertrophy, and other cardiovascular complications.

Preventing and halting progression of left ventricular hypertrophy primarily involves effective blood pressure control, especially in the early stages of ADPKD (Figure 2).

A 7-year prospective randomized trial in ADPKD patients with established hypertension and left ventricular hypertrophy proved that aggressive (< 120/80 mm Hg) compared with standard blood pressure control (135–140/85–90 mm Hg) significantly reduces left ventricular mass index. ACE inhibitors were preferred over calcium channel blockers.⁵⁸

HALT-PKD Study A showed that a significant decrease in left ventricular mass index can be achieved by aggressive blood pressure control (95–110/60–75 mm Hg) with an ACE inhibitor alone or in combination with an ARB in the early stages of ADPKD with preserved renal function.⁴³

A 5-year randomized clinical trial in children with borderline hypertension treated with an ACE inhibitor for effective control of blood pressure showed no change in left ventricular mass index or renal function.^36,59

These results support starting ACE inhibitor therapy early in the disease process when blood pressure is still normal or borderline to prevent the progression of left ventricular hypertrophy or worsening kidney function.

Since FGF23 is directly involved in the causation of left ventricular hypertrophy, FGF receptors may be potential therapeutic targets to prevent left ventricular hypertrophy in ADPKD. An FGF receptor blocker was shown to decrease left ventricular hypertrophy in rats with chronic kidney disease without affecting blood pressure.⁵⁵

INTRACRANIAL ANEURYSM IN ADPKD

Intracranial aneurysm is the most dangerous complication of ADPKD. When an aneurysm ruptures, the mortality rate is 4% to 7%, and 50% of survivors are left with residual neurologic deficits.^5,60,61

In various studies, the prevalence of intracranial aneurysm in ADPKD ranged from 4% to 41.2%, compared with 1% in the general population.^5,62,63 On follow-up ranging from 18 months to about 10 years, the incidence of new intracranial aneurysm was 2.6% to 13.3% in patients with previously normal findings on magnetic resonance angiography and 25% in patients with a history of intracranial aneurysm.^62,64,65

The most common sites are the middle cerebral artery (45%), internal carotid artery (40.5%), and anterior communicating artery (35.1%).⁶⁶ (The numbers add up to more than 100% because some patients have aneurysms in more than 1 site.) The mean size of a ruptured aneurysm was 6 mm per a recent systematic review.⁶⁶ Intracranial aneurysms 6 mm or larger are at highest risk of rupture.⁶⁶

SCREENING FOR INTRACRANIAL ANEURYSM

Timely screening and intervention for intracranial aneurysm is crucial to prevent death from intracranial hemorrhage.

Currently, there are no standard guidelines for screening and follow-up of intracranial aneurysm in ADPKD patients. However, some recommendations are available from the ADPKD Kidney Disease Improving Global Outcomes Controversies Conference³ and Kidney Health Australia—Caring for Australasians With Renal Impairment ADPKD guidelines⁶⁷ (Figure 3).

Imaging tests

Magnetic resonance angiography (MRA) with gadolinium enhancement and computed tomographic angiography (CTA) are recommended for screening in ADPKD patients with normal renal function,⁶⁷ but time-of-flight MRA without gadolinium is the imaging test of choice because it is noninvasive and poses no risk of nephrotoxicity or contrast allergy.^3,68 Further, gadolinium should be avoided in patients whose eGFR is 30 mL/min/1.73 m² or less because of risk of nephrogenic systemic sclerosis and fibrosis.^67,68

The sensitivity of time-of-flight MRA screening for intracranial aneurysm varies depending on the size of aneurysm; 67% for those less than 3 mm, 79% for those 3 to 5 mm, and 95% for those larger than 5 mm.⁶⁹ The sensitivity of CTA screening is 95% for aneurysms larger than 7 mm and 53% for those measuring 2 mm.^70,71 The specificity of CTA screening was reported to be 98.9% overall.⁷¹

When to screen

Screening for intracranial aneurysm is recommended at the time of ADPKD diagnosis for all high-risk patients, ie, those who have a family history of intracranial hemorrhage or aneurysm in an affected first-degree relative.⁶⁷ It is also recommended for ADPKD patients with a history of sudden-onset severe headache or neurologic symptoms.⁶⁷ A third group for whom screening is recommended is ADPKD patients who have no family history of intracranial aneurysm or hemorrhage but who are at risk of poor outcome if an intracranial aneurysm ruptures (eg, those undergoing major elective surgery, with uncontrolled blood pressure, on anticoagulation, with a history of or current smoking, and airline pilots).⁶⁷

Patients found to have an intracranial aneurysm on screening should be referred to a neurosurgeon and should undergo repeat MRA or CTA imaging every 6 to 24 months.³ High-risk ADPKD patients with normal findings on initial screening should have repeat MRA or CTA screening in 5 to 10 years unless they suffer from sudden-onset severe headache or neurologic symptoms.^65,67

Both smoking and high blood pressure increase the risk of formation and growth of intracranial aneurysm. Hence, meticulous control of blood pressure and smoking cessation are recommended in ADPKD patients.^3,67

CARDIAC VALVULAR ABNORMALITIES IN ADPKD

Of the valvular abnormalities that complicate ADPKD, the more common ones are mitral valve prolapse and mitral and aortic regurgitation. The less common ones are tricuspid valve prolapse and tricuspid regurgitation.^72–74

The pathophysiology underlying these valvular abnormalities is unclear. However, defective collagen synthesis and myxomatous degeneration have been demonstrated in histopathologic examination of affected valvular tissue.⁷⁵ Also, ACE gene polymorphism, especially the DD genotype, has been shown to be associated with cardiac valvular calcifications and valvular insufficiency.⁵⁷

Lumiaho et al⁷² found a higher prevalence of mitral valve prolapse, mitral regurgitation, and left ventricular hypertrophy in patients with ADPKD type 1 (due to abnormalities in PDK1) than in unaffected family members and healthy controls. The investigators speculated that mitral regurgitation is caused by the high blood pressure observed in ADPKD type 1 patients, since hypertension causes left ventricular hypertrophy and left ventricular dilatation. The severity of renal failure was related to mitral regurgitation but not mitral valve prolapse.

Similarly, Gabow et al²⁴ showed that there is no significant relationship between mitral valve prolapse and progression of renal disease in ADPKD.

Interestingly, Fick et al²⁰ found that mitral valve prolapse has no significant effect on cardiovascular mortality.

Atherosclerosis sets in early in ADPKD, resulting in coronary artery disease and adverse cardiovascular outcomes.

Coronary flow velocity reserve is the ability of coronary arteries to dilate in response to myocardial oxygen demand. Atherosclerosis decreases this reserve in ADPKD patients, as shown in several studies.

Turkmen et al, in a series of studies,^76–78 found that ADPKD patients had significantly less coronary flow velocity reserve, thicker carotid intima media (a surrogate marker of atherosclerosis), and greater insulin resistance than healthy controls. These findings imply that atherosclerosis begins very early in the course of ADPKD and has remarkable effects on cardiovascular morbidity and mortality.⁷⁶

Aneurysm. Although the risk of extracranial aneurysm is higher with ADPKD, coronary artery aneurysm is uncommon. The pathogenesis of coronary aneurysm has been linked to abnormal expression of the proteins polycystin 1 and polycystin 2 in vascular smooth muscle.^11,79 The PKD1 and PKD2 genes encode polycystin 1 and 2, respectively, in ADPKD. These polycystins are also expressed in the liver, kidneys, and myocardium and are involved in the regulation of intracellular calcium, stretch-activated ion channels, and vascular smooth muscle cell proliferation and apoptosis.^11,16 Abnormally expressed polycystin in ADPKD therefore has an impact on arterial wall integrity, resulting in focal medial defects in the vasculature that eventually develop into micro- and macroaneurysms.¹¹

Hadimeri et al⁷⁹ found a higher prevalence of coronary aneurysm and ectasia in ADPKD patients than in controls. Most coronary aneurysms are smaller than 1 cm; however, a coronary aneurysm measuring 4 cm in diameter was found at autopsy of an ADPKD patient.¹¹

Spontaneous coronary artery dissection is very rare in the general population, but Bobrie et al reported a case of it in an ADPKD patient.⁹

ATRIAL MYXOMA, CARDIOMYOPATHY, AND PERICARDIAL EFFUSION IN ADPKD

Atrial myxoma in ADPKD patients has been described in 2 case reports.^15,80 However, the association of atrial myxoma with ADPKD is poorly understood and may be a coincidental finding.

Cardiomyopathy in ADPKD has been linked to abnormalities in the intracellular calcium pathway, although a clear picture of its involvement has yet to be established.

Paavola et al¹⁶ described the pathophysiology of ADPKD-associated cardiomyopathy in PKD2 mutant zebrafish lacking polycystin 2. These mutants showed decreased cardiac output and had atrioventricular blocks. The findings  were attributed to abnormal intracellular calcium cycling. These findings correlated well with the frequent finding of idiopathic dilated cardiomyopathy in ADPKD patients, especially with PKD2 mutations.¹⁶ Also, 2 cases of dilated cardiomyopathy in ADPKD have been reported and thought to be related to PKD2 mutations.^81,82

Pericardial effusion. Even though the exact pathophysiology of pericardial effusion in ADPKD is unknown, it has been theorized to be related to defects in connective tissue and extracellular matrix due to PKD1 and PKD2 mutations. These abnormalities increase the compliance and impair the recoil capacity of connective tissue, which results in unusual distention of the parietal pericardium. This abnormal distention of the parietal pericardium together with increased extracellular volume may lead to pericardial effusion.¹⁷

Qian et al¹⁷ found a higher prevalence of pericardial effusion in ADPKD patients. It was generally asymptomatic, and the cause was attributed to these connective tissue and extracellular matrix abnormalities.

EMERGING THERAPIES AND TESTS

Recent trials have investigated the effects of vasopressin receptor antagonists, specifically V2 receptor blockers in ADPKD and its complications.

Tolvaptan has been shown to slow the rate of increase in cyst size and total kidney volume.^83,84 Also, a correlation between kidney size and diastolic blood pressure has been observed in ADPKD patients.⁸⁵ Reducing cyst volume may reduce pressure effects and decrease renal ischemia, which in turn may reduce RAAS activation; however, the evidence to support this hypothesis is poor. A major clinical trial of tolvaptan in ADPKD patients showed no effect on blood pressure control, but the drug slowed the rate of increase in total kidney volume and fall in eGFR.⁸³

Endothelin receptor antagonists are also in the preliminary stage of development for use in ADPKD. The effects of acute blockade of the renal endothelial system with bosentan were  investigated in animal models by Hocher et al.²⁸ This study showed a greater reduction in mean arterial pressure after bosentan administration, resulting in significantly decreased GFR and renal blood flow. Nonetheless, the mean arterial pressure-lowering effect of bosentan was more marked than the reductions in GFR and renal blood flow.

Raina et al,⁸⁶ in a pilot cross-sectional analysis, showed that urinary excretion of ET-1 is increased in ADPKD patients, and may serve as a surrogate marker for ET-1 in renal tissue and a noninvasive marker of early kidney injury.

Autosomal dominant polycystic kidney disease (ADPKD) has significant extrarenal manifestations. Hypertension is a common complication, arises early in the course of the disease, and is implicated in the development of left ventricular hypertrophy. Patients with ADPKD are also at risk of other cardiovascular complications (Table 1).

This article reviews the timely diagnosis of these common ADPKD complications and how to manage them.

ADPKD ACCOUNTS FOR 10% OF END-STAGE RENAL DISEASE

ADPKD is a genetic condition characterized by multiple renal cysts.¹ Progressive enlargement of these cysts leads to a gradual decline in kidney function and eventually end-stage renal disease by the fifth or sixth decade of life.² Worldwide, about 12.5 million people have ADPKD, and it accounts for about 10% of cases of end-stage renal disease.^1,3,4

ADPKD has a variety of clinical presentations, including (in decreasing order of frequency) hypertension, flank pain, abdominal masses, urinary tract infection, renal failure, renal stones, and cerebrovascular accidents.²

Extrarenal complications are common and include hepatic cysts, hypertension, left ventricular hypertrophy, valvular heart disease, intracranial and extracranial aneurysms, pancreatic cysts, and diverticulosis.^1–5

Less-common complications are dissection of the aorta and the internal carotid, vertebral, and iliac arteries^6–10; aneurysm of the coronary, popliteal, and splenic arteries^11–14; atrial myxoma¹⁵; cardiomyopathy¹⁶; pericardial effusion¹⁷; intracranial arterial dolichoectasia¹⁸; arachnoid cysts²; and intraoperative inferior vena cava syndrome (normally in ADPKD patients,  pressure on the inferior vena cava results in compensatory sympathetic overactivity to maintain blood pressure), which occurs due to reduced sympathetic output under the influence of epidural or general anesthesia.¹⁹

Cardiovascular complications, especially cardiac hypertrophy and coronary artery disease, are now the leading cause of death in patients with ADPKD, as renal replacement therapy has improved and made death from end-stage renal disease less common.^20,21

HYPERTENSION IN ADPKD

Hypertension is the most frequent initial presentation of ADPKD, occurring in 50% to 75% of cases and usually preceding the onset of renal failure.^2,22 Hypertension is more common in male ADPKD patients, begins early in the course of the disease, and is diagnosed around the fourth decade of life.²¹

In a study in 2007, de Almeida et al²³ used 24-hour ambulatory blood pressure monitoring early in the course of ADPKD and found significantly higher systolic, diastolic, and mean 24-hour blood pressures in ADPKD patients who had normal in-office blood pressure than in normotensive controls. In addition, nighttime systolic, nighttime diastolic, and nighttime mean blood pressures were significantly higher in the ADPKD group. 

Hypertension is strongly associated with an accelerated decline in renal function to end-stage renal disease, development of left ventricular hypertrophy, and cardiovascular death.^20,24

Although a prospective study²⁵ showed a strong association between renal stones and hypertension in ADPKD, the relation between them is not clear. The incidence of renal stones is higher in hypertensive than in normotensive ADPKD patients, although evidence has to be established whether nephro­lithiasis is a risk factor for hypertension or the other way around.²⁵

Hypertension in ADPKD is multifactorial (Figure 1). The major factors associated with its development are increased activation of the renin-angiotensin-aldosterone system (RAAS); overexpression of endothelin receptor subtype A (ET-A) in cystic kidneys; increased production of endothelin 1 (ET-1); and sodium retention.^26–31

The renin-angiotensin-aldosterone system

Activation of the RAAS plays a major role in the development and maintenance of hypertension in ADPKD. This is thought to be mainly due to progressive enlargement of renal cysts, which causes renal arteriolar attenuation and ischemia secondary to pressure effects, which in turn activates the RAAS.^{26,30,32–34} Two studies in patients with normal renal function found that cyst growth and increasing kidney volume have a strong relationship with the development of hypertension and declining kidney function.^35,36

Ectopic secretion of RAAS components in polycystic kidneys has also been implicated in the development of hypertension, whereby renin, angiotensinogen, angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II receptors are produced in the epithelium of cysts and dilated tubules in polycystic kidneys.^37–39 Proximal renal cysts and tubules produce ectopic angiotensinogen, which is converted to angiotensin I by renin in distal renal cysts. Angiotensin I is converted to angiotensin II by ACE in distal tubules, which in turn stimulates angiotensin II receptors, causing sodium and water retention in distal tubules.³⁷ This may be responsible for hypertension in the initial stages; however, RAAS hyperactivity due to renal injury may predominate during later stages.³⁷

Increased RAAS activity also increases sympathetic output, which in turn raises catecholamine levels and blood pressure.³⁴ A study showed higher levels of plasma catecholamines in ADPKD hypertensive patients irrespective of renal function than in patients with essential hypertension.⁴⁰

ET-A receptor and ET-1

A few studies have shown that in ADPKD patients, increased density of ET-A receptors and overproduction of ET-1, a potent vasoconstrictor, play a significant role in the development of hypertension and gradual loss of kidney function due to cyst enlargement and interstitial scarring.^28,29 Ong et al²⁹ found that expression of ET-A receptors is increased in smooth muscle cells of renal arteries, glomerular mesangial cells, and cyst epithelia in ADPKD.

Studies in ADPKD patients with preserved renal function have linked high blood pressure to sodium retention and volume expansion.^30,31,41 However, this phenomenon reverses when there is significant renal impairment in ADPKD.

As evidence of this, a study demonstrated significantly more natriuresis in patients with renal failure due to ADPKD than in patients with a similar degree of renal failure due to chronic glomerulonephritis.³¹ Moreover, another study found that the prevalence of hypertension is higher in ADPKD patients than in those with other nephropathies with preserved renal function, but this association reverses with significant decline in kidney function.²²

MANAGING HYPERTENSION IN ADPKD

Early diagnosis of hypertension and effective control of it, even before ADPKD is diagnosed, is crucial to reduce cardiovascular mortality. Aggressive blood pressure control in the prehypertensive phase of ADPKD will also help reduce the incidence of left ventricular hypertrophy and mitral regurgitation and slow the progression of renal failure (Figure 2).

A meta-analysis⁴² revealed hypertension to be present in 20% of ADPKD patients younger than 21, and many of them were undiagnosed. This study also suggests that patients at risk of hypertension (ie, all patients with ADPKD)  should be routinely screened for it.

Ambulatory blood pressure monitoring may play an important role in diagnosing hypertension early in the prehypertensive stage of ADPKD.²³

Target blood pressures: No consensus

Two well-powered double-blind, placebo-controlled trials, known as HALT-PKD Study A and HALT-PKD Study B, tested the effects of 2 different blood pressure targets and of monotherapy with an ACE inhibitor vs combination therapy with an ACE inhibitor plus an angiotensin II receptor blocker (ARB) on renal function, total kidney volume, left ventricular mass index, and urinary albumin excretion in the early (estimated glomerular filtration rate [eGFR] > 60 mL/min) and late (eGFR 25–60 mL/min) stages of ADPKD, respectively.^43,44

HALT-PKD Study A⁴³ found that, in the early stages of ADPKD with preserved renal function, meticulous control of blood pressure (95–110/60–75 mm Hg) was strongly correlated with significant reductions in left ventricular mass index, albuminuria, and rate of total kidney volume growth without remarkable alteration in renal function compared with standard blood pressure control (120–130/70–80 mm Hg). However, no notable differences were observed between the ACE inhibitor and ACE inhibitor-plus-ARB groups.⁴³

Despite the evidence, universal consensus guidelines are lacking, and the available guidelines on hypertension management have different blood pressure goals in patients with chronic kidney disease.

The eighth Joint National Committee guideline of 2014 recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetic and nondiabetic chronic kidney disease.⁴⁵

The National Institute for Health and Care Excellence 2011 guideline recommends a blood pressure goal of less than 130/80 mm Hg in chronic kidney disease patients.⁴⁶

The European Society of Hypertension and European Society of Cardiology joint 2013 guideline recommends a systolic blood pressure goal of less than 140 mm Hg in diabetic and nondiabetic patients with chronic kidney disease.⁴⁷

The 2016 Kidney Health Australia-Caring for Australians With Renal Impairment guideline for diagnosis and management of ADPKD⁴⁸ recommends a lower blood pressure goal of 96–110/60–75 mm Hg in patients with an eGFR greater than 60 mL/min/1.73 m² who can tolerate it without side effects, which is based on the findings of HALT-PKD Study A.⁴³

Helal et al recommend that blood pressure be controlled to less than 130/80 mm Hg, until there is more evidence for a safe and effective target blood pressure goal in ADPKD patients.⁴⁹

We recommend a target blood pressure less than 110/75 mm Hg in hypertensive ADPKD patients with preserved renal function who can tolerate this level, and less than 130/80 mm Hg in ADPKD patients with stage 3 chronic kidney disease. These targets  can be achieved with ACE inhibitor or ARB monotherapy.^43,44 However, no studies have established the safest lower limit of target blood pressure in ADPKD.

ACE inhibitors, ARBs are mainstays

Mainstays of antihypertensive drug therapy in ADPKD are ACE inhibitors and ARBs.

HALT-PKD Study B⁴⁴ demonstrated that, in the late stages of ADPKD, target blood pressure control (110–130/70–80 mm Hg) can be attained with ACE inhibitor monotherapy or with an ACE inhibitor plus an ARB, but the latter produced no additive benefit.

Patch et al,⁵⁰ in a retrospective cohort study, showed that broadening the spectrum of antihypertensive therapy decreases mortality in ADPKD patients. Evaluating ADPKD patients from the UK General Practice Research Database between 1991 and 2008, they found a trend toward lower mortality rates as the number of antihypertensive drugs prescribed within 1 year increased. They also observed that the prescription of RAAS-blocking agents increased from 7% in 1991 to 46% in 2008.⁵⁰ 

However, a 3-year prospective randomized double-blind study compared the effects of the ACE inhibitor ramipril and the beta-blocker metoprolol in hypertensive ADPKD patients.⁵¹ The results showed that effective blood pressure control could be achieved in both groups with no significant differences in left ventricular mass index, albuminuria, or kidney function.⁵¹

Treatment strategies

Lifestyle modification is the initial approach to the management of hypertension before starting drug therapy. Lifestyle changes include dietary salt restriction to less than 6 g/day, weight reduction, regular exercise, increased fluid intake (up to 3 L/day or to satisfy thirst), smoking cessation, and avoidance of caffeine.^47–49

ACE inhibitors are first-line drugs in hypertensive ADPKD patients.

ARBs can also be considered, but there is no role for dual ACE inhibitor and ARB therapy.^43,48 A study found ACE inhibitors to be more cost-effective and to decrease mortality rates to a greater extent than ARBs.⁵²

Beta-blockers or calcium channel blockers should be considered instead if ACE inhibitors and ARBs are contraindicated,  or as add-on drugs if ACE inhibitors and ARBs fail to reduce blood pressure adequately.^48,49

Diuretics are third-line agents. Thiazides are preferred in ADPKD patients with normal renal function and loop diuretics in those with impaired renal function.⁴⁹

LEFT VENTRICULAR HYPERTROPHY IN ADPKD

Increased left ventricular mass is an indirect indicator of untreated hypertension, and it often goes unnoticed in patients with undiagnosed ADPKD. Left ventricular hypertrophy is associated with arrhythmias and heart failure, which contribute significantly to cardiovascular mortality and adverse renal outcomes.^20,24

A 5-year randomized clinical trial by Cadnapaphornchai et al³⁶ in ADPKD patients between 4 and 21 years of age showed strong correlations between hypertension, left ventricular mass index, and kidney volume and a negative correlation between left ventricular mass index and renal function.

Several factors are thought to contribute to left ventricular hypertrophy in ADPKD (Figure 1).

Hypertension. Two studies of 24-hour ambulatory blood pressure monitoring showed that nocturnal blood pressures decreased less in normotensive and hypertensive ADPKD patients than in normotensive and hypertensive controls.^23,53 This persistent elevation of nocturnal blood pressure may contribute to  the development and progression of left ventricular hypertrophy.

On the other hand, Valero et al⁵⁴ reported that the left ventricular mass index was strongly associated with ambulatory systolic blood pressure rather than elevated nocturnal blood pressure in ADPKD patients compared with healthy controls.

FGF23. High levels of fibroblast growth factor 23 (FGF23) have been shown to be strongly associated with left ventricular hypertrophy in ADPKD. Experimental studies have shown that FGF23 is directly involved in the pathogenesis of left ventricular hypertrophy through stimulation of the calcineurin-nuclear factor of activated T cells pathway.

Faul et al⁵⁵ induced cardiac hypertrophy in mice that were deficient in klotho (a transmembrane protein that increases FGF23 affinity for FGF receptors) by injecting FGF23 intravenously.

Yildiz et al⁵⁶ observed higher levels of FGF23 in hypertensive and normotensive ADPKD patients with normal renal function than in healthy controls. They also found a lower elasticity index in the large and small arteries in normotensive and hypertensive ADPKD patients, which accounts for vascular dysfunction. High FGF23 levels may be responsible for the left ventricular hypertrophy seen in normotensive ADPKD patients with preserved renal function.

Polymorphisms in the ACE gene have been implicated in the development of cardiac hypertrophy in ADPKD.

Wanic-Kossowska et al⁵⁷ studied the association between ACE gene polymorphisms and cardiovascular complications in ADPKD patients. They found a higher prevalence of the homozygous DD genotype among ADPKD patients with end-stage renal disease than in those in the early stages of chronic kidney disease in ADPKD. Also, the DD genotype has been shown to be more strongly associated with left ventricular hypertrophy and left ventricular dysfunction than other (II or ID) genotypes. These findings suggest that the DD genotype carries higher risk for the development of end-stage renal disease, left ventricular hypertrophy, and other cardiovascular complications.

Preventing and halting progression of left ventricular hypertrophy primarily involves effective blood pressure control, especially in the early stages of ADPKD (Figure 2).

A 7-year prospective randomized trial in ADPKD patients with established hypertension and left ventricular hypertrophy proved that aggressive (< 120/80 mm Hg) compared with standard blood pressure control (135–140/85–90 mm Hg) significantly reduces left ventricular mass index. ACE inhibitors were preferred over calcium channel blockers.⁵⁸

HALT-PKD Study A showed that a significant decrease in left ventricular mass index can be achieved by aggressive blood pressure control (95–110/60–75 mm Hg) with an ACE inhibitor alone or in combination with an ARB in the early stages of ADPKD with preserved renal function.⁴³

A 5-year randomized clinical trial in children with borderline hypertension treated with an ACE inhibitor for effective control of blood pressure showed no change in left ventricular mass index or renal function.^36,59

These results support starting ACE inhibitor therapy early in the disease process when blood pressure is still normal or borderline to prevent the progression of left ventricular hypertrophy or worsening kidney function.

Since FGF23 is directly involved in the causation of left ventricular hypertrophy, FGF receptors may be potential therapeutic targets to prevent left ventricular hypertrophy in ADPKD. An FGF receptor blocker was shown to decrease left ventricular hypertrophy in rats with chronic kidney disease without affecting blood pressure.⁵⁵

INTRACRANIAL ANEURYSM IN ADPKD

Intracranial aneurysm is the most dangerous complication of ADPKD. When an aneurysm ruptures, the mortality rate is 4% to 7%, and 50% of survivors are left with residual neurologic deficits.^5,60,61

In various studies, the prevalence of intracranial aneurysm in ADPKD ranged from 4% to 41.2%, compared with 1% in the general population.^5,62,63 On follow-up ranging from 18 months to about 10 years, the incidence of new intracranial aneurysm was 2.6% to 13.3% in patients with previously normal findings on magnetic resonance angiography and 25% in patients with a history of intracranial aneurysm.^62,64,65

The most common sites are the middle cerebral artery (45%), internal carotid artery (40.5%), and anterior communicating artery (35.1%).⁶⁶ (The numbers add up to more than 100% because some patients have aneurysms in more than 1 site.) The mean size of a ruptured aneurysm was 6 mm per a recent systematic review.⁶⁶ Intracranial aneurysms 6 mm or larger are at highest risk of rupture.⁶⁶

SCREENING FOR INTRACRANIAL ANEURYSM

Timely screening and intervention for intracranial aneurysm is crucial to prevent death from intracranial hemorrhage.

Currently, there are no standard guidelines for screening and follow-up of intracranial aneurysm in ADPKD patients. However, some recommendations are available from the ADPKD Kidney Disease Improving Global Outcomes Controversies Conference³ and Kidney Health Australia—Caring for Australasians With Renal Impairment ADPKD guidelines⁶⁷ (Figure 3).

Imaging tests

Magnetic resonance angiography (MRA) with gadolinium enhancement and computed tomographic angiography (CTA) are recommended for screening in ADPKD patients with normal renal function,⁶⁷ but time-of-flight MRA without gadolinium is the imaging test of choice because it is noninvasive and poses no risk of nephrotoxicity or contrast allergy.^3,68 Further, gadolinium should be avoided in patients whose eGFR is 30 mL/min/1.73 m² or less because of risk of nephrogenic systemic sclerosis and fibrosis.^67,68

The sensitivity of time-of-flight MRA screening for intracranial aneurysm varies depending on the size of aneurysm; 67% for those less than 3 mm, 79% for those 3 to 5 mm, and 95% for those larger than 5 mm.⁶⁹ The sensitivity of CTA screening is 95% for aneurysms larger than 7 mm and 53% for those measuring 2 mm.^70,71 The specificity of CTA screening was reported to be 98.9% overall.⁷¹

When to screen

Screening for intracranial aneurysm is recommended at the time of ADPKD diagnosis for all high-risk patients, ie, those who have a family history of intracranial hemorrhage or aneurysm in an affected first-degree relative.⁶⁷ It is also recommended for ADPKD patients with a history of sudden-onset severe headache or neurologic symptoms.⁶⁷ A third group for whom screening is recommended is ADPKD patients who have no family history of intracranial aneurysm or hemorrhage but who are at risk of poor outcome if an intracranial aneurysm ruptures (eg, those undergoing major elective surgery, with uncontrolled blood pressure, on anticoagulation, with a history of or current smoking, and airline pilots).⁶⁷

Patients found to have an intracranial aneurysm on screening should be referred to a neurosurgeon and should undergo repeat MRA or CTA imaging every 6 to 24 months.³ High-risk ADPKD patients with normal findings on initial screening should have repeat MRA or CTA screening in 5 to 10 years unless they suffer from sudden-onset severe headache or neurologic symptoms.^65,67

Both smoking and high blood pressure increase the risk of formation and growth of intracranial aneurysm. Hence, meticulous control of blood pressure and smoking cessation are recommended in ADPKD patients.^3,67

CARDIAC VALVULAR ABNORMALITIES IN ADPKD

Of the valvular abnormalities that complicate ADPKD, the more common ones are mitral valve prolapse and mitral and aortic regurgitation. The less common ones are tricuspid valve prolapse and tricuspid regurgitation.^72–74

The pathophysiology underlying these valvular abnormalities is unclear. However, defective collagen synthesis and myxomatous degeneration have been demonstrated in histopathologic examination of affected valvular tissue.⁷⁵ Also, ACE gene polymorphism, especially the DD genotype, has been shown to be associated with cardiac valvular calcifications and valvular insufficiency.⁵⁷

Lumiaho et al⁷² found a higher prevalence of mitral valve prolapse, mitral regurgitation, and left ventricular hypertrophy in patients with ADPKD type 1 (due to abnormalities in PDK1) than in unaffected family members and healthy controls. The investigators speculated that mitral regurgitation is caused by the high blood pressure observed in ADPKD type 1 patients, since hypertension causes left ventricular hypertrophy and left ventricular dilatation. The severity of renal failure was related to mitral regurgitation but not mitral valve prolapse.

Similarly, Gabow et al²⁴ showed that there is no significant relationship between mitral valve prolapse and progression of renal disease in ADPKD.

Interestingly, Fick et al²⁰ found that mitral valve prolapse has no significant effect on cardiovascular mortality.

Atherosclerosis sets in early in ADPKD, resulting in coronary artery disease and adverse cardiovascular outcomes.

Coronary flow velocity reserve is the ability of coronary arteries to dilate in response to myocardial oxygen demand. Atherosclerosis decreases this reserve in ADPKD patients, as shown in several studies.

Turkmen et al, in a series of studies,^76–78 found that ADPKD patients had significantly less coronary flow velocity reserve, thicker carotid intima media (a surrogate marker of atherosclerosis), and greater insulin resistance than healthy controls. These findings imply that atherosclerosis begins very early in the course of ADPKD and has remarkable effects on cardiovascular morbidity and mortality.⁷⁶

Aneurysm. Although the risk of extracranial aneurysm is higher with ADPKD, coronary artery aneurysm is uncommon. The pathogenesis of coronary aneurysm has been linked to abnormal expression of the proteins polycystin 1 and polycystin 2 in vascular smooth muscle.^11,79 The PKD1 and PKD2 genes encode polycystin 1 and 2, respectively, in ADPKD. These polycystins are also expressed in the liver, kidneys, and myocardium and are involved in the regulation of intracellular calcium, stretch-activated ion channels, and vascular smooth muscle cell proliferation and apoptosis.^11,16 Abnormally expressed polycystin in ADPKD therefore has an impact on arterial wall integrity, resulting in focal medial defects in the vasculature that eventually develop into micro- and macroaneurysms.¹¹

Hadimeri et al⁷⁹ found a higher prevalence of coronary aneurysm and ectasia in ADPKD patients than in controls. Most coronary aneurysms are smaller than 1 cm; however, a coronary aneurysm measuring 4 cm in diameter was found at autopsy of an ADPKD patient.¹¹

Spontaneous coronary artery dissection is very rare in the general population, but Bobrie et al reported a case of it in an ADPKD patient.⁹

ATRIAL MYXOMA, CARDIOMYOPATHY, AND PERICARDIAL EFFUSION IN ADPKD

Atrial myxoma in ADPKD patients has been described in 2 case reports.^15,80 However, the association of atrial myxoma with ADPKD is poorly understood and may be a coincidental finding.

Cardiomyopathy in ADPKD has been linked to abnormalities in the intracellular calcium pathway, although a clear picture of its involvement has yet to be established.

Paavola et al¹⁶ described the pathophysiology of ADPKD-associated cardiomyopathy in PKD2 mutant zebrafish lacking polycystin 2. These mutants showed decreased cardiac output and had atrioventricular blocks. The findings  were attributed to abnormal intracellular calcium cycling. These findings correlated well with the frequent finding of idiopathic dilated cardiomyopathy in ADPKD patients, especially with PKD2 mutations.¹⁶ Also, 2 cases of dilated cardiomyopathy in ADPKD have been reported and thought to be related to PKD2 mutations.^81,82

Pericardial effusion. Even though the exact pathophysiology of pericardial effusion in ADPKD is unknown, it has been theorized to be related to defects in connective tissue and extracellular matrix due to PKD1 and PKD2 mutations. These abnormalities increase the compliance and impair the recoil capacity of connective tissue, which results in unusual distention of the parietal pericardium. This abnormal distention of the parietal pericardium together with increased extracellular volume may lead to pericardial effusion.¹⁷

Qian et al¹⁷ found a higher prevalence of pericardial effusion in ADPKD patients. It was generally asymptomatic, and the cause was attributed to these connective tissue and extracellular matrix abnormalities.

EMERGING THERAPIES AND TESTS

Recent trials have investigated the effects of vasopressin receptor antagonists, specifically V2 receptor blockers in ADPKD and its complications.

Tolvaptan has been shown to slow the rate of increase in cyst size and total kidney volume.^83,84 Also, a correlation between kidney size and diastolic blood pressure has been observed in ADPKD patients.⁸⁵ Reducing cyst volume may reduce pressure effects and decrease renal ischemia, which in turn may reduce RAAS activation; however, the evidence to support this hypothesis is poor. A major clinical trial of tolvaptan in ADPKD patients showed no effect on blood pressure control, but the drug slowed the rate of increase in total kidney volume and fall in eGFR.⁸³

Endothelin receptor antagonists are also in the preliminary stage of development for use in ADPKD. The effects of acute blockade of the renal endothelial system with bosentan were  investigated in animal models by Hocher et al.²⁸ This study showed a greater reduction in mean arterial pressure after bosentan administration, resulting in significantly decreased GFR and renal blood flow. Nonetheless, the mean arterial pressure-lowering effect of bosentan was more marked than the reductions in GFR and renal blood flow.

Raina et al,⁸⁶ in a pilot cross-sectional analysis, showed that urinary excretion of ET-1 is increased in ADPKD patients, and may serve as a surrogate marker for ET-1 in renal tissue and a noninvasive marker of early kidney injury.

Physicians have historically had limited adoption of strategies to improve patient experience and often cite suboptimal data and lack of evidence-driven strategies. ^1,2 However, public reporting of hospital-level physician domain Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) experience scores, and more recent linking of payments to performance on patient experience metrics, have been associated with significant increases in physician domain scores for most of the hospitals. ³ Hospitals and healthcare organizations have deployed a broad range of strategies to engage physicians. These include emphasizing the relationship between patient experience and patient compliance, complaints, and malpractice lawsuits; appealing to physicians’ sense of competitiveness by publishing individual provider experience scores; educating physicians on HCAHPS and providing them with regularly updated data; and development of specific techniques for improving patient-physician interaction. ^4-8

Studies show that educational curricula on improving etiquette and communication skills for physicians lead to improvement in patient experience, and many such training programs are available to hospitals for a significant cost.^9-15 Other studies that have focused on providing timely and individual feedback to physicians using tools other than HCAHPS have shown improvement in experience in some instances. ^16,17 However, these strategies are resource intensive, require the presence of an independent observer in each patient room, and may not be practical in many settings. Further, long-term sustainability may be problematic.

Since the goal of any educational intervention targeting physicians is routinizing best practices, and since resource-intensive strategies of continuous assessment and feedback may not be practical, we sought to test the impact of periodic physician self-reporting of their etiquette-based behavior on their patient experience scores.

Subjects

Hospitalists from 4 hospitals (2 community and 2 academic) that are part of the same healthcare system were the study subjects. Hospitalists who had at least 15 unique patients responding to the routinely administered Press Ganey experience survey during the baseline period were considered eligible. Eligible hospitalists were invited to enroll in the study if their site director confirmed that the provider was likely to stay with the group for the subsequent 12-month study period.

Randomization, Intervention and Control Group

Hospitalists were randomized to the study arm or control arm (1:1 randomization). Study arm participants received biweekly etiquette behavior (EB) surveys and were asked to report how frequently they performed 7 best-practice bedside etiquette behaviors during the previous 2-week period (Table 1). These behaviors were pre-defined by a consensus group of investigators as being amenable to self-report and commonly considered best practice as described in detail below. Control-arm participants received similarly worded survey on quality improvement behaviors (QIB) that would not be expected to impact patient experience (such as reviewing medications to ensure that antithrombotic prophylaxis was prescribed, Table 1).

Baseline and Study Periods

A 12-month period prior to the enrollment of each hospitalist was considered the baseline period for that individual. Hospitalist eligibility was assessed based on number of unique patients for each hospitalist who responded to the survey during this baseline period. Once enrolled, baseline provider-level patient experience scores were calculated based on the survey responses during this 12-month baseline period. Baseline etiquette behavior performance of the study was calculated from the first survey. After the initial survey, hospitalists received biweekly surveys (EB or QIB) for the 12-month study period for a total of 26 surveys (including the initial survey).

Survey Development, Nature of Survey, Survey Distribution Methods

The EB and QIB physician self-report surveys were developed through an iterative process by the study team. The EB survey included elements from an etiquette-based medicine checklist for hospitalized patients described by Kahn et al. ¹⁸ We conducted a review of literature to identify evidence-based practices.^19-22 Research team members contributed items on best practices in etiquette-based medicine from their experience. Specifically, behaviors were selected if they met the following 4 criteria: 1) performing the behavior did not lead to significant increase in workload and was relatively easy to incorporate in the work flow; 2) occurrence of the behavior would be easy to note for any outside observer or the providers themselves; 3) the practice was considered to be either an evidence-based or consensus-based best-practice; 4) there was consensus among study team members on including the item. The survey was tested for understandability by hospitalists who were not eligible for the study.

The EB survey contained 7 items related to behaviors that were expected to impact patient experience. The QIB survey contained 4 items related to behaviors that were expected to improve quality (Table 1). The initial survey also included questions about demographic characteristics of the participants.

Survey questionnaires were sent via email every 2 weeks for a period of 12 months. The survey questionnaire became available every other week, between Friday morning and Tuesday midnight, during the study period. Hospitalists received daily email reminders on each of these days with a link to the survey website if they did not complete the survey. They had the opportunity to report that they were not on service in the prior week and opt out of the survey for the specific 2-week period. The survey questions were available online as well as on a mobile device format.

Provider Level Patient Experience Scores

Provider-level patient experience scores were calculated from the physician domain Press Ganey survey items, which included the time that the physician spent with patients, the physician addressed questions/worries, the physician kept patients informed, the friendliness/courtesy of physician, and the skill of physician. Press Ganey responses were scored from 1 to 5 based on the Likert scale responses on the survey such that a response “very good” was scored 5 and a response “very poor” was scored 1. Additionally, physician domain HCAHPS item (doctors treat with courtesy/respect, doctors listen carefully, doctors explain in way patients understand) responses were utilized to calculate another set of HCAHPS provider level experience scores. The responses were scored as 1 for “always” response and “0” for any other response, consistent with CMS dichotomization of these results for public reporting. Weighted scores were calculated for individual hospitalists based on the proportion of days each hospitalist billed for the hospitalization so that experience scores of patients who were cared for by multiple providers were assigned to each provider in proportion to the percent of care delivered.²³ Separate composite physician scores were generated from the 5 Press Ganey and for the 3 HCAHPS physician items. Each item was weighted equally, with the maximum possible for Press Ganey composite score of 25 (sum of the maximum possible score of 5 on each of the 5 Press Ganey items) and the HCAHPS possible total was 3 (sum of the maximum possible score of 1 on each of the 3 HCAHPS items).

ANALYSIS AND STATISTICAL METHODS

We analyzed the data to assess for changes in frequency of self-reported behavior over the study period, changes in provider-level patient experience between baseline and study period, and the association between the these 2 outcomes. The self-reported etiquette-based behavior responses were scored as 1 for the lowest response (never) to 4 as the highest (always). With 7 questions, the maximum attainable score was 28. The maximum score was normalized to 100 for ease of interpretation (corresponding to percentage of time etiquette behaviors were employed, by self-report). Similarly, the maximum attainable self-reported QIB-related behavior score on the 4 questions was 16. This was also converted to 0-100 scale for ease of comparison.

Two additional sets of analyses were performed to evaluate changes in patient experience during the study period. First, the mean 12-month provider level patient experience composite score in the baseline period was compared with the 12-month composite score during the 12-month study period for the study group and the control group. These were assessed with and without adjusting for age, sex, race, and U.S. medical school graduate (USMG) status. In the second set of unadjusted and adjusted analyses, changes in biweekly composite scores during the study period were compared between the intervention and the control groups while accounting for correlation between observations from the same physician using mixed linear models. Linear mixed models were used to accommodate correlations among multiple observations made on the same physician by including random effects within each regression model. Furthermore, these models allowed us to account for unbalanced design in our data when not all physicians had an equal number of observations and data elements were collected asynchronously.²⁴ Analyses were performed in R version 3.2.2 (The R Project for Statistical Computing, Vienna, Austria); linear mixed models were performed using the ‘nlme’ package.²⁵

We hypothesized that self-reporting on biweekly surveys would result in increases in the frequency of the reported behavior in each arm. We also hypothesized that, because of biweekly reflection and self-reporting on etiquette-based bedside behavior, patient experience scores would increase in the study arm.

Of the 80 hospitalists approached to participate in the study, 64 elected to participate (80% participation rate). The mean response rate to the survey was 57.4% for the intervention arm and 85.7% for the control arm. Higher response rates were not associated with improved patient experience scores. Of the respondents, 43.1% were younger than 35 years of age, 51.5% practiced in academic settings, and 53.1% were female. There was no statistical difference between hospitalists’ baseline composite experience scores based on gender, age, academic hospitalist status, USMG status, and English as a second language status. Similarly, there were no differences in poststudy composite experience scores based on physician characteristics.

Physicians reported high rates of etiquette-based behavior at baseline (mean score, 83.9+/-3.3), and this showed moderate improvement over the study period (5.6 % [3.9%-7.3%, P < 0.0001]). Similarly, there was a moderate increase in frequency of self-reported behavior in the control arm (6.8% [3.5%-10.1%, P < 0.0001]). Hospitalists reported on 80.7% (77.6%-83.4%) of the biweekly surveys that they “almost always” wrapped up by asking, “Do you have any other questions or concerns” or something similar. In contrast, hospitalists reported on only 27.9% (24.7%-31.3%) of the biweekly survey that they “almost always” sat down in the patient room.

The composite physician domain Press Ganey experience scores were no different for the intervention arm and the control arm during the 12-month baseline period (21.8 vs. 21.7; P = 0.90) and the 12-month intervention period (21.6 vs. 21.5; P = 0.75). Baseline self-reported behaviors were not associated with baseline experience scores. Similarly, there were no differences between the arms on composite physician domain HCAHPS experience scores during baseline (2.1 vs. 2.3; P = 0.13) and intervention periods (2.2 vs. 2.1; P = 0.33).

The difference in difference analysis of the baseline and postintervention composite between the intervention arm and the control arm was not statistically significant for Press Ganey composite physician experience scores (-0.163 vs. -0.322; P = 0.71) or HCAHPS composite physician scores (-0.162 vs. -0.071; P = 0.06). The results did not change when controlled for survey response rate (percentage biweekly surveys completed by the hospitalist), age, gender, USMG status, English as a second language status, or percent clinical effort. The difference in difference analysis of the individual Press Ganey and HCAHPS physician domain items that were used to calculate the composite score was also not statistically significant (Table 2).

This 12-month randomized multicenter study of hospitalists showed that repeated self-reporting of etiquette-based behavior results in modest reported increases in performance of these behaviors. However, there was no associated increase in provider level patient experience scores at the end of the study period when compared to baseline scores of the same physicians or when compared to the scores of the control group. The study demonstrated feasibility of self-reporting of behaviors by physicians with high participation when provided modest incentives.

Educational and feedback strategies used to improve patient experience are very resource intensive. Training sessions provided at some hospitals may take hours, and sustained effects are unproved. The presence of an independent observer in patient rooms to generate feedback for providers is not scalable and sustainable outside of a research study environment.^{9-11,15,17,26-29} We attempted to use physician repeated self-reporting to reinforce the important and easy to adopt components of etiquette-based behavior to develop a more easily sustainable strategy. This may have failed for several reasons.

When combining “always” and “usually” responses, the physicians in our study reported a high level of etiquette behavior at baseline. If physicians believe that they are performing well at baseline, they would not consider this to be an area in need of improvement. Bigger changes in behavior may have been possible had the physicians rated themselves less favorably at baseline. Inflated or high baseline self-assessment of performance might also have led to limited success of other types of educational interventions had they been employed.

Studies published since the rollout of our study have shown that physicians significantly overestimate how frequently they perform these etiquette behaviors.^30,31 It is likely that was the case in our study subjects. This may, at best, indicate that a much higher change in the level of self-reported performance would be needed to result in meaningful actual changes, or worse, may render self-reported etiquette behavior entirely unreliable. Interventions designed to improve etiquette-based behavior might need to provide feedback about performance.

A program that provides education on the importance of etiquette-based behaviors, obtains objective measures of performance of these behaviors, and offers individualized feedback may be more likely to increase the desired behaviors. This is a limitation of our study. However, we aimed to test a method that required limited resources. Additionally, our method for attributing HCAHPS scores to an individual physician, based on weighted scores that were calculated according to the proportion of days each hospitalist billed for the hospitalization, may be inaccurate. It is possible that each interaction does not contribute equally to the overall score. A team-based intervention and experience measurements could overcome this limitation.

This randomized trial demonstrated the feasibility of self-assessment of bedside etiquette behaviors by hospitalists but failed to demonstrate a meaningful impact on patient experience through self-report. These findings suggest that more intensive interventions, perhaps involving direct observation, peer-to-peer mentoring, or other techniques may be required to impact significantly physician etiquette behaviors.

Disclosure

Johns Hopkins Hospitalist Scholars Program provided funding support. Dr. Qayyum is a consultant for Sunovion. The other authors have nothing to report.

Physicians have historically had limited adoption of strategies to improve patient experience and often cite suboptimal data and lack of evidence-driven strategies. ^1,2 However, public reporting of hospital-level physician domain Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) experience scores, and more recent linking of payments to performance on patient experience metrics, have been associated with significant increases in physician domain scores for most of the hospitals. ³ Hospitals and healthcare organizations have deployed a broad range of strategies to engage physicians. These include emphasizing the relationship between patient experience and patient compliance, complaints, and malpractice lawsuits; appealing to physicians’ sense of competitiveness by publishing individual provider experience scores; educating physicians on HCAHPS and providing them with regularly updated data; and development of specific techniques for improving patient-physician interaction. ^4-8

Studies show that educational curricula on improving etiquette and communication skills for physicians lead to improvement in patient experience, and many such training programs are available to hospitals for a significant cost.^9-15 Other studies that have focused on providing timely and individual feedback to physicians using tools other than HCAHPS have shown improvement in experience in some instances. ^16,17 However, these strategies are resource intensive, require the presence of an independent observer in each patient room, and may not be practical in many settings. Further, long-term sustainability may be problematic.

Since the goal of any educational intervention targeting physicians is routinizing best practices, and since resource-intensive strategies of continuous assessment and feedback may not be practical, we sought to test the impact of periodic physician self-reporting of their etiquette-based behavior on their patient experience scores.

Subjects

Hospitalists from 4 hospitals (2 community and 2 academic) that are part of the same healthcare system were the study subjects. Hospitalists who had at least 15 unique patients responding to the routinely administered Press Ganey experience survey during the baseline period were considered eligible. Eligible hospitalists were invited to enroll in the study if their site director confirmed that the provider was likely to stay with the group for the subsequent 12-month study period.

Randomization, Intervention and Control Group

Hospitalists were randomized to the study arm or control arm (1:1 randomization). Study arm participants received biweekly etiquette behavior (EB) surveys and were asked to report how frequently they performed 7 best-practice bedside etiquette behaviors during the previous 2-week period (Table 1). These behaviors were pre-defined by a consensus group of investigators as being amenable to self-report and commonly considered best practice as described in detail below. Control-arm participants received similarly worded survey on quality improvement behaviors (QIB) that would not be expected to impact patient experience (such as reviewing medications to ensure that antithrombotic prophylaxis was prescribed, Table 1).

Baseline and Study Periods

A 12-month period prior to the enrollment of each hospitalist was considered the baseline period for that individual. Hospitalist eligibility was assessed based on number of unique patients for each hospitalist who responded to the survey during this baseline period. Once enrolled, baseline provider-level patient experience scores were calculated based on the survey responses during this 12-month baseline period. Baseline etiquette behavior performance of the study was calculated from the first survey. After the initial survey, hospitalists received biweekly surveys (EB or QIB) for the 12-month study period for a total of 26 surveys (including the initial survey).

Survey Development, Nature of Survey, Survey Distribution Methods

The EB and QIB physician self-report surveys were developed through an iterative process by the study team. The EB survey included elements from an etiquette-based medicine checklist for hospitalized patients described by Kahn et al. ¹⁸ We conducted a review of literature to identify evidence-based practices.^19-22 Research team members contributed items on best practices in etiquette-based medicine from their experience. Specifically, behaviors were selected if they met the following 4 criteria: 1) performing the behavior did not lead to significant increase in workload and was relatively easy to incorporate in the work flow; 2) occurrence of the behavior would be easy to note for any outside observer or the providers themselves; 3) the practice was considered to be either an evidence-based or consensus-based best-practice; 4) there was consensus among study team members on including the item. The survey was tested for understandability by hospitalists who were not eligible for the study.

The EB survey contained 7 items related to behaviors that were expected to impact patient experience. The QIB survey contained 4 items related to behaviors that were expected to improve quality (Table 1). The initial survey also included questions about demographic characteristics of the participants.

Survey questionnaires were sent via email every 2 weeks for a period of 12 months. The survey questionnaire became available every other week, between Friday morning and Tuesday midnight, during the study period. Hospitalists received daily email reminders on each of these days with a link to the survey website if they did not complete the survey. They had the opportunity to report that they were not on service in the prior week and opt out of the survey for the specific 2-week period. The survey questions were available online as well as on a mobile device format.

Provider Level Patient Experience Scores

Provider-level patient experience scores were calculated from the physician domain Press Ganey survey items, which included the time that the physician spent with patients, the physician addressed questions/worries, the physician kept patients informed, the friendliness/courtesy of physician, and the skill of physician. Press Ganey responses were scored from 1 to 5 based on the Likert scale responses on the survey such that a response “very good” was scored 5 and a response “very poor” was scored 1. Additionally, physician domain HCAHPS item (doctors treat with courtesy/respect, doctors listen carefully, doctors explain in way patients understand) responses were utilized to calculate another set of HCAHPS provider level experience scores. The responses were scored as 1 for “always” response and “0” for any other response, consistent with CMS dichotomization of these results for public reporting. Weighted scores were calculated for individual hospitalists based on the proportion of days each hospitalist billed for the hospitalization so that experience scores of patients who were cared for by multiple providers were assigned to each provider in proportion to the percent of care delivered.²³ Separate composite physician scores were generated from the 5 Press Ganey and for the 3 HCAHPS physician items. Each item was weighted equally, with the maximum possible for Press Ganey composite score of 25 (sum of the maximum possible score of 5 on each of the 5 Press Ganey items) and the HCAHPS possible total was 3 (sum of the maximum possible score of 1 on each of the 3 HCAHPS items).

ANALYSIS AND STATISTICAL METHODS

We analyzed the data to assess for changes in frequency of self-reported behavior over the study period, changes in provider-level patient experience between baseline and study period, and the association between the these 2 outcomes. The self-reported etiquette-based behavior responses were scored as 1 for the lowest response (never) to 4 as the highest (always). With 7 questions, the maximum attainable score was 28. The maximum score was normalized to 100 for ease of interpretation (corresponding to percentage of time etiquette behaviors were employed, by self-report). Similarly, the maximum attainable self-reported QIB-related behavior score on the 4 questions was 16. This was also converted to 0-100 scale for ease of comparison.

Two additional sets of analyses were performed to evaluate changes in patient experience during the study period. First, the mean 12-month provider level patient experience composite score in the baseline period was compared with the 12-month composite score during the 12-month study period for the study group and the control group. These were assessed with and without adjusting for age, sex, race, and U.S. medical school graduate (USMG) status. In the second set of unadjusted and adjusted analyses, changes in biweekly composite scores during the study period were compared between the intervention and the control groups while accounting for correlation between observations from the same physician using mixed linear models. Linear mixed models were used to accommodate correlations among multiple observations made on the same physician by including random effects within each regression model. Furthermore, these models allowed us to account for unbalanced design in our data when not all physicians had an equal number of observations and data elements were collected asynchronously.²⁴ Analyses were performed in R version 3.2.2 (The R Project for Statistical Computing, Vienna, Austria); linear mixed models were performed using the ‘nlme’ package.²⁵

We hypothesized that self-reporting on biweekly surveys would result in increases in the frequency of the reported behavior in each arm. We also hypothesized that, because of biweekly reflection and self-reporting on etiquette-based bedside behavior, patient experience scores would increase in the study arm.

Of the 80 hospitalists approached to participate in the study, 64 elected to participate (80% participation rate). The mean response rate to the survey was 57.4% for the intervention arm and 85.7% for the control arm. Higher response rates were not associated with improved patient experience scores. Of the respondents, 43.1% were younger than 35 years of age, 51.5% practiced in academic settings, and 53.1% were female. There was no statistical difference between hospitalists’ baseline composite experience scores based on gender, age, academic hospitalist status, USMG status, and English as a second language status. Similarly, there were no differences in poststudy composite experience scores based on physician characteristics.

Physicians reported high rates of etiquette-based behavior at baseline (mean score, 83.9+/-3.3), and this showed moderate improvement over the study period (5.6 % [3.9%-7.3%, P < 0.0001]). Similarly, there was a moderate increase in frequency of self-reported behavior in the control arm (6.8% [3.5%-10.1%, P < 0.0001]). Hospitalists reported on 80.7% (77.6%-83.4%) of the biweekly surveys that they “almost always” wrapped up by asking, “Do you have any other questions or concerns” or something similar. In contrast, hospitalists reported on only 27.9% (24.7%-31.3%) of the biweekly survey that they “almost always” sat down in the patient room.

The composite physician domain Press Ganey experience scores were no different for the intervention arm and the control arm during the 12-month baseline period (21.8 vs. 21.7; P = 0.90) and the 12-month intervention period (21.6 vs. 21.5; P = 0.75). Baseline self-reported behaviors were not associated with baseline experience scores. Similarly, there were no differences between the arms on composite physician domain HCAHPS experience scores during baseline (2.1 vs. 2.3; P = 0.13) and intervention periods (2.2 vs. 2.1; P = 0.33).

The difference in difference analysis of the baseline and postintervention composite between the intervention arm and the control arm was not statistically significant for Press Ganey composite physician experience scores (-0.163 vs. -0.322; P = 0.71) or HCAHPS composite physician scores (-0.162 vs. -0.071; P = 0.06). The results did not change when controlled for survey response rate (percentage biweekly surveys completed by the hospitalist), age, gender, USMG status, English as a second language status, or percent clinical effort. The difference in difference analysis of the individual Press Ganey and HCAHPS physician domain items that were used to calculate the composite score was also not statistically significant (Table 2).

This 12-month randomized multicenter study of hospitalists showed that repeated self-reporting of etiquette-based behavior results in modest reported increases in performance of these behaviors. However, there was no associated increase in provider level patient experience scores at the end of the study period when compared to baseline scores of the same physicians or when compared to the scores of the control group. The study demonstrated feasibility of self-reporting of behaviors by physicians with high participation when provided modest incentives.

Educational and feedback strategies used to improve patient experience are very resource intensive. Training sessions provided at some hospitals may take hours, and sustained effects are unproved. The presence of an independent observer in patient rooms to generate feedback for providers is not scalable and sustainable outside of a research study environment.^{9-11,15,17,26-29} We attempted to use physician repeated self-reporting to reinforce the important and easy to adopt components of etiquette-based behavior to develop a more easily sustainable strategy. This may have failed for several reasons.

When combining “always” and “usually” responses, the physicians in our study reported a high level of etiquette behavior at baseline. If physicians believe that they are performing well at baseline, they would not consider this to be an area in need of improvement. Bigger changes in behavior may have been possible had the physicians rated themselves less favorably at baseline. Inflated or high baseline self-assessment of performance might also have led to limited success of other types of educational interventions had they been employed.

Studies published since the rollout of our study have shown that physicians significantly overestimate how frequently they perform these etiquette behaviors.^30,31 It is likely that was the case in our study subjects. This may, at best, indicate that a much higher change in the level of self-reported performance would be needed to result in meaningful actual changes, or worse, may render self-reported etiquette behavior entirely unreliable. Interventions designed to improve etiquette-based behavior might need to provide feedback about performance.

A program that provides education on the importance of etiquette-based behaviors, obtains objective measures of performance of these behaviors, and offers individualized feedback may be more likely to increase the desired behaviors. This is a limitation of our study. However, we aimed to test a method that required limited resources. Additionally, our method for attributing HCAHPS scores to an individual physician, based on weighted scores that were calculated according to the proportion of days each hospitalist billed for the hospitalization, may be inaccurate. It is possible that each interaction does not contribute equally to the overall score. A team-based intervention and experience measurements could overcome this limitation.

This randomized trial demonstrated the feasibility of self-assessment of bedside etiquette behaviors by hospitalists but failed to demonstrate a meaningful impact on patient experience through self-report. These findings suggest that more intensive interventions, perhaps involving direct observation, peer-to-peer mentoring, or other techniques may be required to impact significantly physician etiquette behaviors.

Disclosure

Johns Hopkins Hospitalist Scholars Program provided funding support. Dr. Qayyum is a consultant for Sunovion. The other authors have nothing to report.

Physicians have historically had limited adoption of strategies to improve patient experience and often cite suboptimal data and lack of evidence-driven strategies. ^1,2 However, public reporting of hospital-level physician domain Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) experience scores, and more recent linking of payments to performance on patient experience metrics, have been associated with significant increases in physician domain scores for most of the hospitals. ³ Hospitals and healthcare organizations have deployed a broad range of strategies to engage physicians. These include emphasizing the relationship between patient experience and patient compliance, complaints, and malpractice lawsuits; appealing to physicians’ sense of competitiveness by publishing individual provider experience scores; educating physicians on HCAHPS and providing them with regularly updated data; and development of specific techniques for improving patient-physician interaction. ^4-8

Studies show that educational curricula on improving etiquette and communication skills for physicians lead to improvement in patient experience, and many such training programs are available to hospitals for a significant cost.^9-15 Other studies that have focused on providing timely and individual feedback to physicians using tools other than HCAHPS have shown improvement in experience in some instances. ^16,17 However, these strategies are resource intensive, require the presence of an independent observer in each patient room, and may not be practical in many settings. Further, long-term sustainability may be problematic.

Since the goal of any educational intervention targeting physicians is routinizing best practices, and since resource-intensive strategies of continuous assessment and feedback may not be practical, we sought to test the impact of periodic physician self-reporting of their etiquette-based behavior on their patient experience scores.

Subjects

Hospitalists from 4 hospitals (2 community and 2 academic) that are part of the same healthcare system were the study subjects. Hospitalists who had at least 15 unique patients responding to the routinely administered Press Ganey experience survey during the baseline period were considered eligible. Eligible hospitalists were invited to enroll in the study if their site director confirmed that the provider was likely to stay with the group for the subsequent 12-month study period.

Randomization, Intervention and Control Group

Hospitalists were randomized to the study arm or control arm (1:1 randomization). Study arm participants received biweekly etiquette behavior (EB) surveys and were asked to report how frequently they performed 7 best-practice bedside etiquette behaviors during the previous 2-week period (Table 1). These behaviors were pre-defined by a consensus group of investigators as being amenable to self-report and commonly considered best practice as described in detail below. Control-arm participants received similarly worded survey on quality improvement behaviors (QIB) that would not be expected to impact patient experience (such as reviewing medications to ensure that antithrombotic prophylaxis was prescribed, Table 1).

Baseline and Study Periods

A 12-month period prior to the enrollment of each hospitalist was considered the baseline period for that individual. Hospitalist eligibility was assessed based on number of unique patients for each hospitalist who responded to the survey during this baseline period. Once enrolled, baseline provider-level patient experience scores were calculated based on the survey responses during this 12-month baseline period. Baseline etiquette behavior performance of the study was calculated from the first survey. After the initial survey, hospitalists received biweekly surveys (EB or QIB) for the 12-month study period for a total of 26 surveys (including the initial survey).

Survey Development, Nature of Survey, Survey Distribution Methods

The EB and QIB physician self-report surveys were developed through an iterative process by the study team. The EB survey included elements from an etiquette-based medicine checklist for hospitalized patients described by Kahn et al. ¹⁸ We conducted a review of literature to identify evidence-based practices.^19-22 Research team members contributed items on best practices in etiquette-based medicine from their experience. Specifically, behaviors were selected if they met the following 4 criteria: 1) performing the behavior did not lead to significant increase in workload and was relatively easy to incorporate in the work flow; 2) occurrence of the behavior would be easy to note for any outside observer or the providers themselves; 3) the practice was considered to be either an evidence-based or consensus-based best-practice; 4) there was consensus among study team members on including the item. The survey was tested for understandability by hospitalists who were not eligible for the study.

The EB survey contained 7 items related to behaviors that were expected to impact patient experience. The QIB survey contained 4 items related to behaviors that were expected to improve quality (Table 1). The initial survey also included questions about demographic characteristics of the participants.

Survey questionnaires were sent via email every 2 weeks for a period of 12 months. The survey questionnaire became available every other week, between Friday morning and Tuesday midnight, during the study period. Hospitalists received daily email reminders on each of these days with a link to the survey website if they did not complete the survey. They had the opportunity to report that they were not on service in the prior week and opt out of the survey for the specific 2-week period. The survey questions were available online as well as on a mobile device format.

Provider Level Patient Experience Scores

Provider-level patient experience scores were calculated from the physician domain Press Ganey survey items, which included the time that the physician spent with patients, the physician addressed questions/worries, the physician kept patients informed, the friendliness/courtesy of physician, and the skill of physician. Press Ganey responses were scored from 1 to 5 based on the Likert scale responses on the survey such that a response “very good” was scored 5 and a response “very poor” was scored 1. Additionally, physician domain HCAHPS item (doctors treat with courtesy/respect, doctors listen carefully, doctors explain in way patients understand) responses were utilized to calculate another set of HCAHPS provider level experience scores. The responses were scored as 1 for “always” response and “0” for any other response, consistent with CMS dichotomization of these results for public reporting. Weighted scores were calculated for individual hospitalists based on the proportion of days each hospitalist billed for the hospitalization so that experience scores of patients who were cared for by multiple providers were assigned to each provider in proportion to the percent of care delivered.²³ Separate composite physician scores were generated from the 5 Press Ganey and for the 3 HCAHPS physician items. Each item was weighted equally, with the maximum possible for Press Ganey composite score of 25 (sum of the maximum possible score of 5 on each of the 5 Press Ganey items) and the HCAHPS possible total was 3 (sum of the maximum possible score of 1 on each of the 3 HCAHPS items).

ANALYSIS AND STATISTICAL METHODS

We analyzed the data to assess for changes in frequency of self-reported behavior over the study period, changes in provider-level patient experience between baseline and study period, and the association between the these 2 outcomes. The self-reported etiquette-based behavior responses were scored as 1 for the lowest response (never) to 4 as the highest (always). With 7 questions, the maximum attainable score was 28. The maximum score was normalized to 100 for ease of interpretation (corresponding to percentage of time etiquette behaviors were employed, by self-report). Similarly, the maximum attainable self-reported QIB-related behavior score on the 4 questions was 16. This was also converted to 0-100 scale for ease of comparison.

Two additional sets of analyses were performed to evaluate changes in patient experience during the study period. First, the mean 12-month provider level patient experience composite score in the baseline period was compared with the 12-month composite score during the 12-month study period for the study group and the control group. These were assessed with and without adjusting for age, sex, race, and U.S. medical school graduate (USMG) status. In the second set of unadjusted and adjusted analyses, changes in biweekly composite scores during the study period were compared between the intervention and the control groups while accounting for correlation between observations from the same physician using mixed linear models. Linear mixed models were used to accommodate correlations among multiple observations made on the same physician by including random effects within each regression model. Furthermore, these models allowed us to account for unbalanced design in our data when not all physicians had an equal number of observations and data elements were collected asynchronously.²⁴ Analyses were performed in R version 3.2.2 (The R Project for Statistical Computing, Vienna, Austria); linear mixed models were performed using the ‘nlme’ package.²⁵

We hypothesized that self-reporting on biweekly surveys would result in increases in the frequency of the reported behavior in each arm. We also hypothesized that, because of biweekly reflection and self-reporting on etiquette-based bedside behavior, patient experience scores would increase in the study arm.

Of the 80 hospitalists approached to participate in the study, 64 elected to participate (80% participation rate). The mean response rate to the survey was 57.4% for the intervention arm and 85.7% for the control arm. Higher response rates were not associated with improved patient experience scores. Of the respondents, 43.1% were younger than 35 years of age, 51.5% practiced in academic settings, and 53.1% were female. There was no statistical difference between hospitalists’ baseline composite experience scores based on gender, age, academic hospitalist status, USMG status, and English as a second language status. Similarly, there were no differences in poststudy composite experience scores based on physician characteristics.

Physicians reported high rates of etiquette-based behavior at baseline (mean score, 83.9+/-3.3), and this showed moderate improvement over the study period (5.6 % [3.9%-7.3%, P < 0.0001]). Similarly, there was a moderate increase in frequency of self-reported behavior in the control arm (6.8% [3.5%-10.1%, P < 0.0001]). Hospitalists reported on 80.7% (77.6%-83.4%) of the biweekly surveys that they “almost always” wrapped up by asking, “Do you have any other questions or concerns” or something similar. In contrast, hospitalists reported on only 27.9% (24.7%-31.3%) of the biweekly survey that they “almost always” sat down in the patient room.

The composite physician domain Press Ganey experience scores were no different for the intervention arm and the control arm during the 12-month baseline period (21.8 vs. 21.7; P = 0.90) and the 12-month intervention period (21.6 vs. 21.5; P = 0.75). Baseline self-reported behaviors were not associated with baseline experience scores. Similarly, there were no differences between the arms on composite physician domain HCAHPS experience scores during baseline (2.1 vs. 2.3; P = 0.13) and intervention periods (2.2 vs. 2.1; P = 0.33).

The difference in difference analysis of the baseline and postintervention composite between the intervention arm and the control arm was not statistically significant for Press Ganey composite physician experience scores (-0.163 vs. -0.322; P = 0.71) or HCAHPS composite physician scores (-0.162 vs. -0.071; P = 0.06). The results did not change when controlled for survey response rate (percentage biweekly surveys completed by the hospitalist), age, gender, USMG status, English as a second language status, or percent clinical effort. The difference in difference analysis of the individual Press Ganey and HCAHPS physician domain items that were used to calculate the composite score was also not statistically significant (Table 2).

This 12-month randomized multicenter study of hospitalists showed that repeated self-reporting of etiquette-based behavior results in modest reported increases in performance of these behaviors. However, there was no associated increase in provider level patient experience scores at the end of the study period when compared to baseline scores of the same physicians or when compared to the scores of the control group. The study demonstrated feasibility of self-reporting of behaviors by physicians with high participation when provided modest incentives.

Educational and feedback strategies used to improve patient experience are very resource intensive. Training sessions provided at some hospitals may take hours, and sustained effects are unproved. The presence of an independent observer in patient rooms to generate feedback for providers is not scalable and sustainable outside of a research study environment.^{9-11,15,17,26-29} We attempted to use physician repeated self-reporting to reinforce the important and easy to adopt components of etiquette-based behavior to develop a more easily sustainable strategy. This may have failed for several reasons.

When combining “always” and “usually” responses, the physicians in our study reported a high level of etiquette behavior at baseline. If physicians believe that they are performing well at baseline, they would not consider this to be an area in need of improvement. Bigger changes in behavior may have been possible had the physicians rated themselves less favorably at baseline. Inflated or high baseline self-assessment of performance might also have led to limited success of other types of educational interventions had they been employed.

Studies published since the rollout of our study have shown that physicians significantly overestimate how frequently they perform these etiquette behaviors.^30,31 It is likely that was the case in our study subjects. This may, at best, indicate that a much higher change in the level of self-reported performance would be needed to result in meaningful actual changes, or worse, may render self-reported etiquette behavior entirely unreliable. Interventions designed to improve etiquette-based behavior might need to provide feedback about performance.

A program that provides education on the importance of etiquette-based behaviors, obtains objective measures of performance of these behaviors, and offers individualized feedback may be more likely to increase the desired behaviors. This is a limitation of our study. However, we aimed to test a method that required limited resources. Additionally, our method for attributing HCAHPS scores to an individual physician, based on weighted scores that were calculated according to the proportion of days each hospitalist billed for the hospitalization, may be inaccurate. It is possible that each interaction does not contribute equally to the overall score. A team-based intervention and experience measurements could overcome this limitation.

This randomized trial demonstrated the feasibility of self-assessment of bedside etiquette behaviors by hospitalists but failed to demonstrate a meaningful impact on patient experience through self-report. These findings suggest that more intensive interventions, perhaps involving direct observation, peer-to-peer mentoring, or other techniques may be required to impact significantly physician etiquette behaviors.

Disclosure

Johns Hopkins Hospitalist Scholars Program provided funding support. Dr. Qayyum is a consultant for Sunovion. The other authors have nothing to report.

To the Editor: In their Clinical Picture article in the February 2017 issue, Barbaryan et al¹ describe brain lesions in a young woman with human immunodeficiency virus infection who presented with seizures. Figure 3 illustrates Grocott-Gomori methenamine silver (GMS)-positive fungal organisms in a brain biopsy. The organisms appear helmet-shaped and crescent-shaped and contain an intracystic dot, morphologic features of Pneumocystis jiroveci cysts.² We could not appreciate features of Histoplasma yeasts (smaller yeasts with diameter of 3 to 5 μm, oval to tapered shape, and narrow-based budding).

The distinction between the two organisms can occasionally be challenging because there is some degree of overlap in size and shape, and both are GMS-positive. It is interesting that in the current case, serologic studies for Histoplasma were positive. Multiple infections with opportunistic organisms are not uncommon in severely immunocompromised individuals, and it is possible that the patient may also have had concurrent histoplasmosis. Brain lesions caused by Pneumocystis, although rare, have been previously reported.^3–5 Immunohistochemistry for Pneumocystis may be of interest in this very unusual case.

[Editor’s note: Letters that comment on articles published in the Journal are sent to the author(s) for response. In this case, the authors felt that the letter did not require a reply.]

To the Editor: In their Clinical Picture article in the February 2017 issue, Barbaryan et al¹ describe brain lesions in a young woman with human immunodeficiency virus infection who presented with seizures. Figure 3 illustrates Grocott-Gomori methenamine silver (GMS)-positive fungal organisms in a brain biopsy. The organisms appear helmet-shaped and crescent-shaped and contain an intracystic dot, morphologic features of Pneumocystis jiroveci cysts.² We could not appreciate features of Histoplasma yeasts (smaller yeasts with diameter of 3 to 5 μm, oval to tapered shape, and narrow-based budding).

The distinction between the two organisms can occasionally be challenging because there is some degree of overlap in size and shape, and both are GMS-positive. It is interesting that in the current case, serologic studies for Histoplasma were positive. Multiple infections with opportunistic organisms are not uncommon in severely immunocompromised individuals, and it is possible that the patient may also have had concurrent histoplasmosis. Brain lesions caused by Pneumocystis, although rare, have been previously reported.^3–5 Immunohistochemistry for Pneumocystis may be of interest in this very unusual case.

[Editor’s note: Letters that comment on articles published in the Journal are sent to the author(s) for response. In this case, the authors felt that the letter did not require a reply.]

To the Editor: In their Clinical Picture article in the February 2017 issue, Barbaryan et al¹ describe brain lesions in a young woman with human immunodeficiency virus infection who presented with seizures. Figure 3 illustrates Grocott-Gomori methenamine silver (GMS)-positive fungal organisms in a brain biopsy. The organisms appear helmet-shaped and crescent-shaped and contain an intracystic dot, morphologic features of Pneumocystis jiroveci cysts.² We could not appreciate features of Histoplasma yeasts (smaller yeasts with diameter of 3 to 5 μm, oval to tapered shape, and narrow-based budding).

The distinction between the two organisms can occasionally be challenging because there is some degree of overlap in size and shape, and both are GMS-positive. It is interesting that in the current case, serologic studies for Histoplasma were positive. Multiple infections with opportunistic organisms are not uncommon in severely immunocompromised individuals, and it is possible that the patient may also have had concurrent histoplasmosis. Brain lesions caused by Pneumocystis, although rare, have been previously reported.^3–5 Immunohistochemistry for Pneumocystis may be of interest in this very unusual case.

[Editor’s note: Letters that comment on articles published in the Journal are sent to the author(s) for response. In this case, the authors felt that the letter did not require a reply.]