Social distancing measures instituted during the ­COVID-19 pandemic challenged the usual way of operating in primary care. To continue delivering medical services, physicians had to transition quickly to forms of remote interaction with patients. Use of technology appeared to be the answer. And it gave clinicians the ability to do what many had long hoped for: offer patients the option of telehealth.

The terms telemedicine and telehealth have similar definitions and are commonly used interchangeably. We think most practices probably would have adopted telehealth earlier were it not for reimbursement barriers. In this article, we adopt the World Health Organization’s definition of telemedicine as: “The delivery of healthcare services, where distance is a critical factor, by all healthcare professionals using information and communication technologies for the exchange of valid information for the diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of healthcare providers, all in the interests of advancing the health of individuals and their communities.”¹

To provide family medicine clinicians with evidence-based recommendations about telehealth, we conducted a critical review of the literature published through April 30, 2021. The scope of this review includes studies found using the PubMed and Google Scholar databases. In addition, we used the keywords “telehealth,” “telemedicine,” “family medicine,” and “primary care.” We divided this review into 6 sections, including focus areas on implementation in primary care, remote diagnostic accuracy, conditions lending themselves to telehealth, physician and patient perceptions, disparities in telehealth, and finally, the conclusions.

Telehealth implementation in primary care

Telehealth in various forms had been around for years before the pandemic, mainly in the form of commercial telehealth businesses. Telehealth was being used in rural and remote areas where it could be difficult to see a primary care provider—let alone a specialist. The family medicine department of the University of Colorado was an early adopter of telehealth and had navigated this transition since 2017, with clinical champions guiding the process. By 2019, 54% of their clinicians were conducting telehealth encounters.²

However, telehealth implementation elsewhere was not accepted so readily. Before the pandemic, a cross-sectional study of more than 1.1 million patients in Northern California showed that 86% preferred in-­person care over video.³ Even as the pandemic began and social distancing measures were implemented, a quality improvement project at a family medicine residency clinic in Florida documented that clinicians still preferred telephone interviews despite the capacity for video visits.⁴ And many primary care systems were simply unprepared to adopt telehealth technologies.

With time, however, family physicians began to improvise using popular videoconferencing technologies (eg, Zoom) that were readily available and familiar to patients, and medical centers began to repurpose their existing videoconferencing systems.⁵ The Ohio State University Wexner Medical Center launched a virtual health initiative just before the pandemic struck, at which time fewer than 5% of patient visits were conducted through telehealth. Weeks later, nearly 93% of patient visits were offered through telehealth.⁶

Reimbursement. Another significant impediment to early telehealth uptake was the late reaction by the Centers for Medicare and Medicaid Services (CMS) in changing the payment system. Hectic expansion of telehealth in response to the crisis pointed to the lack of policies that supported primary care with payments based on outcomes rather than fee-for-service models.⁷ By the end of April 2020, CMS finally announced that video visits would be reimbursed at the same rate as in-person visits. However, telephone-only visits are still very limited in coverage, and appropriate codes should be verified with payers.

Continue to: Remote diagnosis comes with a caveat

Remote diagnosis comes with a caveat

Some primary care practices have found that images of skin lesions submitted by patients (usually by cell phone) suffice for accurate diagnosis in lieu of office visits.⁸ With chronic conditions, home-based remote monitoring of vital signs may assist in diagnosing and managing acute issues. More efficient triage of patients is increasingly possible with the receipt of still images or video files of concerning lesions (eg, burns, rash, chronic wounds) sent from smartphones alone^9,10 or with devices attached to smartphones (eg, parent-managed otoscopes).^11,12

CMS reimburses for video visits at the same rate it does for in-person visits, but telephone-only visits are still limited in coverage.

Family physicians historically have relied on in-person visits for holistic assessment and diagnosis. Telehealth video visits have the potential to assist with this goal, but there are risks. For example, one patient cut her foot while swimming and the wound became infected. In a video telehealth visit with a physician assistant, the patient was prescribed an oral antibiotic for cellulitis. However, redness and swelling of the wound continued to increase. Subsequent messages left by the patient went unheeded, and she then visited her local emergency department where she received intravenous antibiotics.¹³ Another patient, who had cervical neck discomfort, had a video visit with an urgent care clinic. The initial diagnosis was sciatica; however, the pain continued with the addition of chills, sweats, and subjective fever.¹⁴ Physical examination at the hospital and lab tests revealed endocarditis. These case reports show the limitations of video visits.

Specific conditions usually suitable for telehealth evaluation

The pandemic helped us understand that some situations and conditions are better suited than others to coverage by telehealth. The National Ambulatory Medical Care Survey examined 850 million patient–­physician encounters and found that 66% of all ambulatory primary care visits required in-­office care,¹⁵ suggesting that about one-third of patient encounters could be treated via ­telehealth.

As an example, our southeastern Wisconsin urban clinic has about 20,000 office visits per year. We launched telehealth in March 2020 in direct response to the pandemic. Telehealth usage peaked at the beginning of the pandemic (FIGURE), fell gradually, hit a lower peak in November and December as COVID case counts increased, and then decreased again as our community changed from a “quarantine/lockdown” mentality to “opening up/back to new normal.”

Some conditions can be managed favorably with the telehealth format:

Infectious diseases may be treatable remotely.^16,17 Following an initial telehealth visit, the physician can evaluate and recommend further care.

Stable, chronic conditions. Telehealth can be used for stable, chronic conditions such as diabetes, chronic obstructive pulmonary disease, and heart failure when lab or imaging studies are not needed.¹⁸

Mental health. Telehealth can be useful in counseling and providing mental health and social support.¹⁸ Safeguards can be put in place to protect patient privacy in this setting.¹⁹

Behavioral change. Telehealth can be effective in providing support for patients actively trying to quit smoking or lose weight, and for caregivers. A physician who “checks in” can be a positive motivator and can promote a patient’s continued success.²⁰

Continue to: Telehealth is less beneficial...

Telehealth is less beneficial when a physical exam is needed to assess pain, tenderness, strength, or other sensations. Office visits also are required for lab assays and imaging, as in periodic checks of A1C levels in patients with diabetes. As technology advances, home-based laboratory kits and sensors likely will change this picture. New patients may be better served through an initial office visit to develop the patient–physician relationship.

Visual assessment of conditions may be limited by telehealth depending on the quality of the devices used. For example, rashes may be difficult to assess given the clarity of the picture on the device and the ability to see only in 2D. There is still a need for more controlled trials to clarify which conditions can be evaluated and managed by telehealth and which ones need in-person care.²¹

Physician and patient perceptions of telehealth encounters

Research into family physicians’ perceptions of telehealth is scant. However, 3 studies published in 2021 reveal some advantages and challenges for telehealth adoption.

• A qualitative study found that physicians valued the increased access to care for some patients, changes to reimbursement practices not covered before, and the opportunity to see patients’ home environments.²² Disadvantages included an inability to examine the patient, problems with diagnostic accuracy, hindrances to developing personal connections, and the potential for burnout with on-demand care.²² The researchers suggested that telehealth might better serve to augment in-person care.
• A second study found that clinicians are satisfied with the use of telehealth in general. However, it also noted that the lack of physical examination could hinder accurate diagnosis and treatment.²³
• A third study surveyed 109 family physicians, reinforcing the importance of physical exams and highlighting the lack of body language as another barrier.²⁴

In addition, all 3 studies noted that video visits are typically briefer than in-person visits. Previous research predominantly done in specialty and mental health care showed that the benefits of telehealth for physicians include an increase in efficiency, reduced commute time, and improved work-life balance.²⁵

Patient perspectives. Many patients have reported that they prefer telehealth because of lower costs, decreased travel time, and faster health care access.^26,27 However, patients also have expressed concerns that the telehealth environment may reduce physician attention, can limit personal interaction (and impart a sense of being rushed), and lacks the physical examination that may be key to an adequate diagnosis.²⁸

Continue to: A survey of 223 patients showed...

A survey of 223 patients showed that sicker patients choose in-person care because they want more in-depth visits with more attention to detail than healthier patients do.²⁹ In a Veterans Affairs health care system qualitative study, patients voiced concerns about communicating with physicians via telehealth, including the potential for errors, less attention paid to their needs, audio difficulties, and challenges to establishing a physician–patient relationship.³⁰ Some patients thought telehealth inhibited their personal expression or that the clinician was not attentive enough. These patient reports underscore the importance of patient–clinician relationships developed in person.³¹ The perceived level of complexity involved in a visit appears to be an essential factor in a patient opting for telehealth—or not.

Efficient triage of patients is increasingly possible with still images or videos sent from smartphones.

In light of these known physician and patient perspectives, it seems wise to develop a hybrid model approach in which visits alternate between telehealth and office.

Patient disparities that may limit the use of telehealth

Race and ethnicity is a major factor in telehealth use. Patients who are Black or Hispanic use telehealth services less often than patients who are White.^32,33 A study that looked at patients with chronic conditions—hypertension and diabetes—that disproportionately affect Black and Hispanic patients found that patients in these populations with either of these conditions had a lower prevalence of Internet use when compared with White patients.³⁴ However, subpopulations can vary in their usage. For example, a study in East Harlem, New York, found that Hispanic pregnant women used telehealth frequently for prenatal care and perceived the care as satisfactory.³⁵

Age is also a significant variable in the adoption of telehealth, with pre-­COVID-19 studies finding lower use of technology among older adults. However, a study performed at the University of Missouri during the first months of the pandemic found an increase in telehealth use in seniors,³² although the increase was in telephone use and not full video sessions.

Many patients in need of health care services may have older devices and/or low-speed or no Internet access; they also may lack the technical know-how to conduct a telehealth visit.^4,36 For example, regardless of race or ethnicity, patients on government insurance (Medicaid and Medicare) have been shown to complete more telephone than video visits,³⁷ underscoring the importance of telehealth practice flexibility and the need for increased technology support to decrease the digital divide. Even with adequate technological support and patient training, telehealth may be more complicated if patients have such comorbidities as hearing, visual, or cognitive impairment.³¹ Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.³⁸

Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.

Overall, incorporating telehealth for the care of older and/or vulnerable patients will present a unique set of challenges that organizations must address. Efforts must be made to understand the available technologies and patients’ comfort in using them. A hybrid model offering telehealth and in-office encounters may be the best solution.

CORRESPONDENCE
Hernan Barenboim, PhD, KPC Health Group, 301 North San Jacinto Street, Hemet, CA 92543; [email protected]

Social distancing measures instituted during the ­COVID-19 pandemic challenged the usual way of operating in primary care. To continue delivering medical services, physicians had to transition quickly to forms of remote interaction with patients. Use of technology appeared to be the answer. And it gave clinicians the ability to do what many had long hoped for: offer patients the option of telehealth.

The terms telemedicine and telehealth have similar definitions and are commonly used interchangeably. We think most practices probably would have adopted telehealth earlier were it not for reimbursement barriers. In this article, we adopt the World Health Organization’s definition of telemedicine as: “The delivery of healthcare services, where distance is a critical factor, by all healthcare professionals using information and communication technologies for the exchange of valid information for the diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of healthcare providers, all in the interests of advancing the health of individuals and their communities.”¹

To provide family medicine clinicians with evidence-based recommendations about telehealth, we conducted a critical review of the literature published through April 30, 2021. The scope of this review includes studies found using the PubMed and Google Scholar databases. In addition, we used the keywords “telehealth,” “telemedicine,” “family medicine,” and “primary care.” We divided this review into 6 sections, including focus areas on implementation in primary care, remote diagnostic accuracy, conditions lending themselves to telehealth, physician and patient perceptions, disparities in telehealth, and finally, the conclusions.

Telehealth implementation in primary care

Telehealth in various forms had been around for years before the pandemic, mainly in the form of commercial telehealth businesses. Telehealth was being used in rural and remote areas where it could be difficult to see a primary care provider—let alone a specialist. The family medicine department of the University of Colorado was an early adopter of telehealth and had navigated this transition since 2017, with clinical champions guiding the process. By 2019, 54% of their clinicians were conducting telehealth encounters.²

However, telehealth implementation elsewhere was not accepted so readily. Before the pandemic, a cross-sectional study of more than 1.1 million patients in Northern California showed that 86% preferred in-­person care over video.³ Even as the pandemic began and social distancing measures were implemented, a quality improvement project at a family medicine residency clinic in Florida documented that clinicians still preferred telephone interviews despite the capacity for video visits.⁴ And many primary care systems were simply unprepared to adopt telehealth technologies.

With time, however, family physicians began to improvise using popular videoconferencing technologies (eg, Zoom) that were readily available and familiar to patients, and medical centers began to repurpose their existing videoconferencing systems.⁵ The Ohio State University Wexner Medical Center launched a virtual health initiative just before the pandemic struck, at which time fewer than 5% of patient visits were conducted through telehealth. Weeks later, nearly 93% of patient visits were offered through telehealth.⁶

Reimbursement. Another significant impediment to early telehealth uptake was the late reaction by the Centers for Medicare and Medicaid Services (CMS) in changing the payment system. Hectic expansion of telehealth in response to the crisis pointed to the lack of policies that supported primary care with payments based on outcomes rather than fee-for-service models.⁷ By the end of April 2020, CMS finally announced that video visits would be reimbursed at the same rate as in-person visits. However, telephone-only visits are still very limited in coverage, and appropriate codes should be verified with payers.

Continue to: Remote diagnosis comes with a caveat

Remote diagnosis comes with a caveat

Some primary care practices have found that images of skin lesions submitted by patients (usually by cell phone) suffice for accurate diagnosis in lieu of office visits.⁸ With chronic conditions, home-based remote monitoring of vital signs may assist in diagnosing and managing acute issues. More efficient triage of patients is increasingly possible with the receipt of still images or video files of concerning lesions (eg, burns, rash, chronic wounds) sent from smartphones alone^9,10 or with devices attached to smartphones (eg, parent-managed otoscopes).^11,12

CMS reimburses for video visits at the same rate it does for in-person visits, but telephone-only visits are still limited in coverage.

Family physicians historically have relied on in-person visits for holistic assessment and diagnosis. Telehealth video visits have the potential to assist with this goal, but there are risks. For example, one patient cut her foot while swimming and the wound became infected. In a video telehealth visit with a physician assistant, the patient was prescribed an oral antibiotic for cellulitis. However, redness and swelling of the wound continued to increase. Subsequent messages left by the patient went unheeded, and she then visited her local emergency department where she received intravenous antibiotics.¹³ Another patient, who had cervical neck discomfort, had a video visit with an urgent care clinic. The initial diagnosis was sciatica; however, the pain continued with the addition of chills, sweats, and subjective fever.¹⁴ Physical examination at the hospital and lab tests revealed endocarditis. These case reports show the limitations of video visits.

Specific conditions usually suitable for telehealth evaluation

The pandemic helped us understand that some situations and conditions are better suited than others to coverage by telehealth. The National Ambulatory Medical Care Survey examined 850 million patient–­physician encounters and found that 66% of all ambulatory primary care visits required in-­office care,¹⁵ suggesting that about one-third of patient encounters could be treated via ­telehealth.

As an example, our southeastern Wisconsin urban clinic has about 20,000 office visits per year. We launched telehealth in March 2020 in direct response to the pandemic. Telehealth usage peaked at the beginning of the pandemic (FIGURE), fell gradually, hit a lower peak in November and December as COVID case counts increased, and then decreased again as our community changed from a “quarantine/lockdown” mentality to “opening up/back to new normal.”

Some conditions can be managed favorably with the telehealth format:

Infectious diseases may be treatable remotely.^16,17 Following an initial telehealth visit, the physician can evaluate and recommend further care.

Stable, chronic conditions. Telehealth can be used for stable, chronic conditions such as diabetes, chronic obstructive pulmonary disease, and heart failure when lab or imaging studies are not needed.¹⁸

Mental health. Telehealth can be useful in counseling and providing mental health and social support.¹⁸ Safeguards can be put in place to protect patient privacy in this setting.¹⁹

Behavioral change. Telehealth can be effective in providing support for patients actively trying to quit smoking or lose weight, and for caregivers. A physician who “checks in” can be a positive motivator and can promote a patient’s continued success.²⁰

Continue to: Telehealth is less beneficial...

Telehealth is less beneficial when a physical exam is needed to assess pain, tenderness, strength, or other sensations. Office visits also are required for lab assays and imaging, as in periodic checks of A1C levels in patients with diabetes. As technology advances, home-based laboratory kits and sensors likely will change this picture. New patients may be better served through an initial office visit to develop the patient–physician relationship.

Visual assessment of conditions may be limited by telehealth depending on the quality of the devices used. For example, rashes may be difficult to assess given the clarity of the picture on the device and the ability to see only in 2D. There is still a need for more controlled trials to clarify which conditions can be evaluated and managed by telehealth and which ones need in-person care.²¹

Physician and patient perceptions of telehealth encounters

Research into family physicians’ perceptions of telehealth is scant. However, 3 studies published in 2021 reveal some advantages and challenges for telehealth adoption.

• A qualitative study found that physicians valued the increased access to care for some patients, changes to reimbursement practices not covered before, and the opportunity to see patients’ home environments.²² Disadvantages included an inability to examine the patient, problems with diagnostic accuracy, hindrances to developing personal connections, and the potential for burnout with on-demand care.²² The researchers suggested that telehealth might better serve to augment in-person care.
• A second study found that clinicians are satisfied with the use of telehealth in general. However, it also noted that the lack of physical examination could hinder accurate diagnosis and treatment.²³
• A third study surveyed 109 family physicians, reinforcing the importance of physical exams and highlighting the lack of body language as another barrier.²⁴

In addition, all 3 studies noted that video visits are typically briefer than in-person visits. Previous research predominantly done in specialty and mental health care showed that the benefits of telehealth for physicians include an increase in efficiency, reduced commute time, and improved work-life balance.²⁵

Patient perspectives. Many patients have reported that they prefer telehealth because of lower costs, decreased travel time, and faster health care access.^26,27 However, patients also have expressed concerns that the telehealth environment may reduce physician attention, can limit personal interaction (and impart a sense of being rushed), and lacks the physical examination that may be key to an adequate diagnosis.²⁸

Continue to: A survey of 223 patients showed...

A survey of 223 patients showed that sicker patients choose in-person care because they want more in-depth visits with more attention to detail than healthier patients do.²⁹ In a Veterans Affairs health care system qualitative study, patients voiced concerns about communicating with physicians via telehealth, including the potential for errors, less attention paid to their needs, audio difficulties, and challenges to establishing a physician–patient relationship.³⁰ Some patients thought telehealth inhibited their personal expression or that the clinician was not attentive enough. These patient reports underscore the importance of patient–clinician relationships developed in person.³¹ The perceived level of complexity involved in a visit appears to be an essential factor in a patient opting for telehealth—or not.

Efficient triage of patients is increasingly possible with still images or videos sent from smartphones.

In light of these known physician and patient perspectives, it seems wise to develop a hybrid model approach in which visits alternate between telehealth and office.

Patient disparities that may limit the use of telehealth

Race and ethnicity is a major factor in telehealth use. Patients who are Black or Hispanic use telehealth services less often than patients who are White.^32,33 A study that looked at patients with chronic conditions—hypertension and diabetes—that disproportionately affect Black and Hispanic patients found that patients in these populations with either of these conditions had a lower prevalence of Internet use when compared with White patients.³⁴ However, subpopulations can vary in their usage. For example, a study in East Harlem, New York, found that Hispanic pregnant women used telehealth frequently for prenatal care and perceived the care as satisfactory.³⁵

Age is also a significant variable in the adoption of telehealth, with pre-­COVID-19 studies finding lower use of technology among older adults. However, a study performed at the University of Missouri during the first months of the pandemic found an increase in telehealth use in seniors,³² although the increase was in telephone use and not full video sessions.

Many patients in need of health care services may have older devices and/or low-speed or no Internet access; they also may lack the technical know-how to conduct a telehealth visit.^4,36 For example, regardless of race or ethnicity, patients on government insurance (Medicaid and Medicare) have been shown to complete more telephone than video visits,³⁷ underscoring the importance of telehealth practice flexibility and the need for increased technology support to decrease the digital divide. Even with adequate technological support and patient training, telehealth may be more complicated if patients have such comorbidities as hearing, visual, or cognitive impairment.³¹ Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.³⁸

Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.

Overall, incorporating telehealth for the care of older and/or vulnerable patients will present a unique set of challenges that organizations must address. Efforts must be made to understand the available technologies and patients’ comfort in using them. A hybrid model offering telehealth and in-office encounters may be the best solution.

CORRESPONDENCE
Hernan Barenboim, PhD, KPC Health Group, 301 North San Jacinto Street, Hemet, CA 92543; [email protected]

Social distancing measures instituted during the ­COVID-19 pandemic challenged the usual way of operating in primary care. To continue delivering medical services, physicians had to transition quickly to forms of remote interaction with patients. Use of technology appeared to be the answer. And it gave clinicians the ability to do what many had long hoped for: offer patients the option of telehealth.

The terms telemedicine and telehealth have similar definitions and are commonly used interchangeably. We think most practices probably would have adopted telehealth earlier were it not for reimbursement barriers. In this article, we adopt the World Health Organization’s definition of telemedicine as: “The delivery of healthcare services, where distance is a critical factor, by all healthcare professionals using information and communication technologies for the exchange of valid information for the diagnosis, treatment, and prevention of disease and injuries, research and evaluation, and for the continuing education of healthcare providers, all in the interests of advancing the health of individuals and their communities.”¹

To provide family medicine clinicians with evidence-based recommendations about telehealth, we conducted a critical review of the literature published through April 30, 2021. The scope of this review includes studies found using the PubMed and Google Scholar databases. In addition, we used the keywords “telehealth,” “telemedicine,” “family medicine,” and “primary care.” We divided this review into 6 sections, including focus areas on implementation in primary care, remote diagnostic accuracy, conditions lending themselves to telehealth, physician and patient perceptions, disparities in telehealth, and finally, the conclusions.

Telehealth implementation in primary care

Telehealth in various forms had been around for years before the pandemic, mainly in the form of commercial telehealth businesses. Telehealth was being used in rural and remote areas where it could be difficult to see a primary care provider—let alone a specialist. The family medicine department of the University of Colorado was an early adopter of telehealth and had navigated this transition since 2017, with clinical champions guiding the process. By 2019, 54% of their clinicians were conducting telehealth encounters.²

However, telehealth implementation elsewhere was not accepted so readily. Before the pandemic, a cross-sectional study of more than 1.1 million patients in Northern California showed that 86% preferred in-­person care over video.³ Even as the pandemic began and social distancing measures were implemented, a quality improvement project at a family medicine residency clinic in Florida documented that clinicians still preferred telephone interviews despite the capacity for video visits.⁴ And many primary care systems were simply unprepared to adopt telehealth technologies.

With time, however, family physicians began to improvise using popular videoconferencing technologies (eg, Zoom) that were readily available and familiar to patients, and medical centers began to repurpose their existing videoconferencing systems.⁵ The Ohio State University Wexner Medical Center launched a virtual health initiative just before the pandemic struck, at which time fewer than 5% of patient visits were conducted through telehealth. Weeks later, nearly 93% of patient visits were offered through telehealth.⁶

Reimbursement. Another significant impediment to early telehealth uptake was the late reaction by the Centers for Medicare and Medicaid Services (CMS) in changing the payment system. Hectic expansion of telehealth in response to the crisis pointed to the lack of policies that supported primary care with payments based on outcomes rather than fee-for-service models.⁷ By the end of April 2020, CMS finally announced that video visits would be reimbursed at the same rate as in-person visits. However, telephone-only visits are still very limited in coverage, and appropriate codes should be verified with payers.

Continue to: Remote diagnosis comes with a caveat

Remote diagnosis comes with a caveat

Some primary care practices have found that images of skin lesions submitted by patients (usually by cell phone) suffice for accurate diagnosis in lieu of office visits.⁸ With chronic conditions, home-based remote monitoring of vital signs may assist in diagnosing and managing acute issues. More efficient triage of patients is increasingly possible with the receipt of still images or video files of concerning lesions (eg, burns, rash, chronic wounds) sent from smartphones alone^9,10 or with devices attached to smartphones (eg, parent-managed otoscopes).^11,12

CMS reimburses for video visits at the same rate it does for in-person visits, but telephone-only visits are still limited in coverage.

Family physicians historically have relied on in-person visits for holistic assessment and diagnosis. Telehealth video visits have the potential to assist with this goal, but there are risks. For example, one patient cut her foot while swimming and the wound became infected. In a video telehealth visit with a physician assistant, the patient was prescribed an oral antibiotic for cellulitis. However, redness and swelling of the wound continued to increase. Subsequent messages left by the patient went unheeded, and she then visited her local emergency department where she received intravenous antibiotics.¹³ Another patient, who had cervical neck discomfort, had a video visit with an urgent care clinic. The initial diagnosis was sciatica; however, the pain continued with the addition of chills, sweats, and subjective fever.¹⁴ Physical examination at the hospital and lab tests revealed endocarditis. These case reports show the limitations of video visits.

Specific conditions usually suitable for telehealth evaluation

The pandemic helped us understand that some situations and conditions are better suited than others to coverage by telehealth. The National Ambulatory Medical Care Survey examined 850 million patient–­physician encounters and found that 66% of all ambulatory primary care visits required in-­office care,¹⁵ suggesting that about one-third of patient encounters could be treated via ­telehealth.

As an example, our southeastern Wisconsin urban clinic has about 20,000 office visits per year. We launched telehealth in March 2020 in direct response to the pandemic. Telehealth usage peaked at the beginning of the pandemic (FIGURE), fell gradually, hit a lower peak in November and December as COVID case counts increased, and then decreased again as our community changed from a “quarantine/lockdown” mentality to “opening up/back to new normal.”

Some conditions can be managed favorably with the telehealth format:

Infectious diseases may be treatable remotely.^16,17 Following an initial telehealth visit, the physician can evaluate and recommend further care.

Stable, chronic conditions. Telehealth can be used for stable, chronic conditions such as diabetes, chronic obstructive pulmonary disease, and heart failure when lab or imaging studies are not needed.¹⁸

Mental health. Telehealth can be useful in counseling and providing mental health and social support.¹⁸ Safeguards can be put in place to protect patient privacy in this setting.¹⁹

Behavioral change. Telehealth can be effective in providing support for patients actively trying to quit smoking or lose weight, and for caregivers. A physician who “checks in” can be a positive motivator and can promote a patient’s continued success.²⁰

Continue to: Telehealth is less beneficial...

Telehealth is less beneficial when a physical exam is needed to assess pain, tenderness, strength, or other sensations. Office visits also are required for lab assays and imaging, as in periodic checks of A1C levels in patients with diabetes. As technology advances, home-based laboratory kits and sensors likely will change this picture. New patients may be better served through an initial office visit to develop the patient–physician relationship.

Visual assessment of conditions may be limited by telehealth depending on the quality of the devices used. For example, rashes may be difficult to assess given the clarity of the picture on the device and the ability to see only in 2D. There is still a need for more controlled trials to clarify which conditions can be evaluated and managed by telehealth and which ones need in-person care.²¹

Physician and patient perceptions of telehealth encounters

Research into family physicians’ perceptions of telehealth is scant. However, 3 studies published in 2021 reveal some advantages and challenges for telehealth adoption.

• A qualitative study found that physicians valued the increased access to care for some patients, changes to reimbursement practices not covered before, and the opportunity to see patients’ home environments.²² Disadvantages included an inability to examine the patient, problems with diagnostic accuracy, hindrances to developing personal connections, and the potential for burnout with on-demand care.²² The researchers suggested that telehealth might better serve to augment in-person care.
• A second study found that clinicians are satisfied with the use of telehealth in general. However, it also noted that the lack of physical examination could hinder accurate diagnosis and treatment.²³
• A third study surveyed 109 family physicians, reinforcing the importance of physical exams and highlighting the lack of body language as another barrier.²⁴

In addition, all 3 studies noted that video visits are typically briefer than in-person visits. Previous research predominantly done in specialty and mental health care showed that the benefits of telehealth for physicians include an increase in efficiency, reduced commute time, and improved work-life balance.²⁵

Patient perspectives. Many patients have reported that they prefer telehealth because of lower costs, decreased travel time, and faster health care access.^26,27 However, patients also have expressed concerns that the telehealth environment may reduce physician attention, can limit personal interaction (and impart a sense of being rushed), and lacks the physical examination that may be key to an adequate diagnosis.²⁸

Continue to: A survey of 223 patients showed...

A survey of 223 patients showed that sicker patients choose in-person care because they want more in-depth visits with more attention to detail than healthier patients do.²⁹ In a Veterans Affairs health care system qualitative study, patients voiced concerns about communicating with physicians via telehealth, including the potential for errors, less attention paid to their needs, audio difficulties, and challenges to establishing a physician–patient relationship.³⁰ Some patients thought telehealth inhibited their personal expression or that the clinician was not attentive enough. These patient reports underscore the importance of patient–clinician relationships developed in person.³¹ The perceived level of complexity involved in a visit appears to be an essential factor in a patient opting for telehealth—or not.

Efficient triage of patients is increasingly possible with still images or videos sent from smartphones.

In light of these known physician and patient perspectives, it seems wise to develop a hybrid model approach in which visits alternate between telehealth and office.

Patient disparities that may limit the use of telehealth

Race and ethnicity is a major factor in telehealth use. Patients who are Black or Hispanic use telehealth services less often than patients who are White.^32,33 A study that looked at patients with chronic conditions—hypertension and diabetes—that disproportionately affect Black and Hispanic patients found that patients in these populations with either of these conditions had a lower prevalence of Internet use when compared with White patients.³⁴ However, subpopulations can vary in their usage. For example, a study in East Harlem, New York, found that Hispanic pregnant women used telehealth frequently for prenatal care and perceived the care as satisfactory.³⁵

Age is also a significant variable in the adoption of telehealth, with pre-­COVID-19 studies finding lower use of technology among older adults. However, a study performed at the University of Missouri during the first months of the pandemic found an increase in telehealth use in seniors,³² although the increase was in telephone use and not full video sessions.

Many patients in need of health care services may have older devices and/or low-speed or no Internet access; they also may lack the technical know-how to conduct a telehealth visit.^4,36 For example, regardless of race or ethnicity, patients on government insurance (Medicaid and Medicare) have been shown to complete more telephone than video visits,³⁷ underscoring the importance of telehealth practice flexibility and the need for increased technology support to decrease the digital divide. Even with adequate technological support and patient training, telehealth may be more complicated if patients have such comorbidities as hearing, visual, or cognitive impairment.³¹ Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.³⁸

Patients from a lower socioeconomic status may feel uncomfortable with providers seeing their home environment on video.

Overall, incorporating telehealth for the care of older and/or vulnerable patients will present a unique set of challenges that organizations must address. Efforts must be made to understand the available technologies and patients’ comfort in using them. A hybrid model offering telehealth and in-office encounters may be the best solution.

CORRESPONDENCE
Hernan Barenboim, PhD, KPC Health Group, 301 North San Jacinto Street, Hemet, CA 92543; [email protected]

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediatorsthat enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93).The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03).However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001).The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma.Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediatorsthat enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93).The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03).However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001).The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma.Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediatorsthat enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93).The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03).However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001).The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma.Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

CHICAGO – Nearly 60% of health care providers surveyed failed to choose the same treatment strategies for HER2– early breast cancer as a panel of five oncologists with expertise in breast cancer, a new study finds.

The discrepancy suggests that many providers aren’t aware of the findings of recent landmark trials that formed the basis of the panel’s opinions, said study coauthor Denise A. Yardley, MD, of Tennessee Oncology and Sarah Cannon Research Institute in Nashville, in an interview. The findings, based on responses to a treatment decision tool, were presented in a poster at the annual meeting of the American Society of Clinical Oncology.

Study methods and results

For the new study, researchers analyzed how 547 providers – and the panel – responded to 10 case scenarios in high-risk HER2– early breast cancer between June 2022 and January 2023.

Among the providers surveyed, 72% identified as physicians, including oncologists, hematologists/oncologists, surgery oncologists, radiation oncologists, and pathologists. One percent said they were nurse practitioners or physician assistants, 7% said they were pharmacists, 1% were nurses, and the specific roles of the remaining 19% were unknown, but included medical students, according to Dr. Yardley, who is a breast cancer oncologist.

The study authors developed the free decision tool – available via the medical education company Clinical Care Options – to help oncologists navigate new treatment options for high-risk HER2– early breast cancer. The Food and Drug Administration has recently approved drugs such as abemaciclib, olaparib, and pembrolizumab for the condition.

Health care providers enter details into the tool about their patients along with their intended treatment plans. The tool then shows them recommendations for treatment from a panel of five oncologists with expertise in oncology. The members of the panel based their perspectives on the findings of the KEYNOTE-522 (pembrolizumab), OlympiA (olaparib), and monarchE (abemaciclib) trials.

The oncologists with expertise in breast cancer, who provided recommendations in March 2022, generally agreed about the best treatments, Dr. Yardley said.

The other health care providers surveyed didn’t agree with the breast cancer experts about the best treatment 58.8% of the time.

For example, one scenario describes a HR+, HER2– patient with no deleterious BRCA mutation – or unknown status – who fits the monarchE high-risk criteria. All the breast cancer experts on the panel recommended abemaciclib and endocrine therapy. But 203 providers supported a variety of strategies: endocrine therapy alone (9%), chemotherapy followed by endocrine therapy (49%), and olaparib and endocrine therapy (2%). Only 37% opted for abemaciclib and endocrine therapy, and 4% were uncertain.

Another scenario describes a patient with triple-negative breast cancer with no residual disease after neoadjuvant chemotherapy. All the experts agreed on a strategy of no adjuvant therapy plus observation. Forty percent of 25 providers agreed with this approach, but 24% were uncertain, 12% chose pembrolizumab, and 24% chose capecitabine.

In many cases, providers chose more intensive treatment options than the experts did, Dr. Yardley said.

Overtreatment in cancer is often a reflex for oncologists, she said, although “we’re learning to deescalate these treatment algorithms where there is really no benefit [to extra treatment].”

“It’s a challenge for some of these oncologists who are busy and dealing with multiple solid tumor types to keep up with the nuances of a rapidly changing field,” Dr. Yardley noted.

Many community oncologists aren’t specialists in one type of cancer and must try to keep up with treatment recommendations regarding multiple types, she continued.
 

Decision tool’s value explained

According to the study, 32% of providers changed their treatment choices in clinical practice after they learned about the expert perspectives via the decision tool; 46% said the expert opinions confirmed that their choices were best practice.

The value of the tool is its ability to help providers make better decisions about patient care, Dr. Yardley said. “There seems to be a need for this kind of support.”

In an interview, University of Pittsburgh Medical Center oncologist Adam M. Brufsky, MD, PhD – who wasn’t involved with the study – said he was surprised by the amount of disagreement between the expert and provider perspectives on treatment. However, he noted that community oncologists – unlike the breast cancer experts – often don’t see just one type of cancer.

“You just have to know so much now as an oncologist,” Dr. Brufsky said. He recommended that colleagues take advantage of decision support tools, such as cancer treatment pathways.

The study was funded by AstraZeneca, Lilly, and Merck Sharp & Dohme. Dr. Yardley has no disclosures, and disclosure information from other authors was not available. Dr. Brufsky discloses consulting support from AstraZeneca, Lilly, and Merck and grants from AstraZeneca.

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Patients with acute promyelocytic leukemia (APL) – previously considered among the most rapidly fatal forms of acute myeloid leukemia (AML) – now show survival rates exceeding 90% at 10 years after treatment with a chemotherapy-free regimen of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), with a survival advantage over ATRA plus chemotherapy in low- and intermediate-risk patients.

“In a large cohort of patients with APL, the chemo-free combination of ATRA/ATO is confirmed as the best treatment option, prolonging overall and event-free survival and reducing the relapse rate compared with ATRA/chemotherapy,” said first author Maria Teresa Voso, MD, of Tor Vergata University, in Rome, in presenting the findings at the 2023 annual meeting of the European Hematology Association.

APL, though rare, makes up about 10% of new AML cases, and the advent of the chemo-free ATRA-ATO regimen in recent years has transformed the disease, significantly improving survival.

However, with ongoing questions regarding factors associated with treatment benefits based on issues including the level of risk, Dr. Voso and colleagues turned to data from the large European Union–funded HARMONY registry, a big data project that uniquely provides real-world as well as clinical trial findings from diverse APL patient populations.

They identified 937 patients in the registry with newly diagnosed APL between 2007 and 2020 who met the study’s data quality criteria, including 536 (57.2%) patients from two clinical trials, the UK AML-17 and GIMEMA APL0406 trials, and 401 (42.8%) patients from national registries in 6 countries, representing real-world data.

The median duration of follow-up was 5.66 years, with a range of 0-14 years.

The patients had an average age of about 50, which is consistent with the lower age of diagnosis typical of APL, compared with other forms of AML.

Among them, 380 (40.6%) were treated with the ATRA-ATO regimen while 509 (54.3%) received the chemotherapy combination of ATRA-Idarubicin (AIDA).

Overall, 37.8% were determined to be low risk, as assessed by the Sanz risk-score; 42.3% were intermediate risk, and 18.7% were considered high risk. The rate of complete remission among the patients was 87.5%, and 9% had relapsed.

The results showed the 10-year overall survival (OS) rate to be 92% among the chemo-free ATRA-ATO-treated patients versus 75% in the AIDA-treated patients (P = .001).

Likewise, those treated with the chemo-free regimen had a higher event-free survival and a lower cumulative incidence of relapse (CIR) versus chemotherapy over 10 years (P < .001 for both).

In further stratifying by risk, patients who were low risk also had greater improvements with the chemo-free regimen in overall survival (P = .004), event-free survival, and CIR versus AIDA treatment (P < .001).

Among high-risk patients, however, only event-free survival was significantly improved in the chemo-free treated patients (P = .046).

Older age stood out as a significant determinant of survival, with patients in the age 50-69 and 70 or over age groups having a significantly lower rate of overall survival and event-free survival, compared with those under 50 years of age (P < .001), with those risks observed regardless of treatment type.

Age was not a significant factor in terms of the incidence of relapse (P = .159).
 

Clinical trial versus real-world outcomes

Of note, improved outcomes were reported in clinical trials versus real-world data, with overall survival higher in clinical trials among patients receiving the ATRA/ATO chemo-free treatment (P = .025), as well as in those receiving the AIDA chemotherapy (P < .001).

Early death, an uncommon but key concern with APL, usually due to bleeding complications and defined as death occurring within 30 days from APL diagnosis, occurred among 56 patients, or 5.9%, overall, and was significantly higher in the age 50-69 and over 70 groups versus those under 50 (P < .001).

Early death was more common among those with a Sanz high-risk score (15.4%), compared with low or intermediate risk (3.9%; P < .001); however, the risk was no different between the chemo-free (3.4%) and chemotherapy (5.7%) groups, regardless of whether patients had a low or high risk.

The rates of early death were significantly higher in the real-world population (10.2%), compared with patients in clinical trials (2.8%; P < .001), which Dr. Voso noted may be expected, as early deaths in some cases can occur even before a diagnosis is made.

“These patients sometimes come to the ER and if a diagnosis is not made, they may die before even receiving treatment,” she said in a press briefing.

“Indeed, the median time to death among those who had early death in the study was only 10 days, and there were even some patients dying at day 0,” she explained.

“So, it’s very important that not only hematologists but emergency doctors recognize this disease and try to reduce the early death rate.”

Overall, the results all remained consistent after adjustment in a multivariate analysis, Dr. Voso said.

“The multivariate analysis confirmed that increasing age, high Sanz risk score, the real-life treatment scenario, and the chemotherapy-based approach are independently associated with decreased survival,” she said.

The findings underscore that “elderly age and high Sanz risk score significantly impact on the rate of early deaths, irrespective of treatment,” Dr. Voso said.
 

ATRA/ATO ‘gold standard’ for low/intermediate risk

Commenting on the study, Alessandro Isidori, MD, PhD, a hematologist at AORMN Hospital, in Pesaro, Italy, who moderated the session, noted that the study underscores the greater challenges with higher-risk patients.

“The study did not show a statistical benefit for high-risk patients receiving ATRA/ATO versus AIDA,” he told this news organization, noting that “currently, there are many countries where ATRA/ATO is not approved for use in high-risk APL.”

“In high-risk APL, the AIDA combination should still be preferred to ATRA/ATO,” he said.

Dr. Isidori recommended careful efforts to stratify higher-risk patients who still may benefit from ATRA/ATO.

“The analysis of high-risk patients with white blood cell count as a continuous variable instead of a fixed variable (more or less than 10,000/mmc) may help to discriminate some high-risk patients who could benefit from ATRA/ATO,” he noted.

Overall, however, “ATRA/ATO is the gold standard for low and intermediate risk APL,” he said.

“Although promising, more data are needed to confirm the efficacy of ATRA/ATO in high-risk APL.”

Dr. Voso disclosed ties with companies including Celgene/Bristol Myers Squibb, Astellas, Jazz Pharmaceuticals, Abbvie, Novartis, and AstraZeneca. Dr. Isidori reported no disclosures.
 

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

Despite new options in non–hormone-based treatments, hormone therapy remains the most effective treatment for vasomotor symptoms (VMS) and should be considered for healthy menopausal women without contraindications within 10 years of their final menstrual periods.

This recommendation emerged from an updated position statement from the North American Menopause Society in its first review of the scientific literature since 2015. The statement specifically targets nonhormonal management of symptoms such as hot flashes and night sweats, which occur in as many as 80% of menopausal women but are undertreated. The statement appears in the June issue of the Journal of The North American Menopause Society.

“Women with contraindications or objections to hormone treatment should be informed by professionals of evidence-based effective nonhormone treatment options,” stated a NAMS advisory panel led by Chrisandra L. Shufelt, MD, MS, professor and chair of the division of general internal medicine and associate director of the Women’s Health Research Center at the Mayo Clinic in Jacksonville, Fla. The statement is one of multiple NAMS updates performed at regular intervals, said Dr. Shufelt, also past president of NAMS, in an interview. “But the research has changed, and we wanted to make clinicians aware of new medications. One of our interesting findings was more evidence that off-label use of the nonhormonal overactive bladder drug oxybutynin can lower the rate of hot flashes.”

Dr. Shufelt noted that many of the current update’s findings align with previous research, and stressed that the therapeutic recommendations apply specifically to VMS. “Not all menopause-related symptoms are vasomotor, however,” she said. “While a lot of the lifestyle options such as cooling techniques and exercise are not recommended for controlling hot flashes, diet and exercise changes can be beneficial for other health reasons.”

Although it’s the most effective option for VMS, hormone therapy is not suitable for women with contraindications such as a previous blood clot, an estrogen-dependent cancer, a family history of such cancers, or a personal preference against hormone use, Dr. Shufelt added, so nonhormonal alternatives are important to prevent women from wasting time and money on ineffective remedies. “Women need to know what works and what doesn’t,” she said.
 

Recommended nonhormonal therapies

Based on a rigorous review of the scientific evidence to date, NAMS found the following therapies to be effective: cognitive-behavioral therapy; clinical hypnosis; SSRIs and serotonin-norepinephrine reuptake inhibitors – which yield mild to moderate improvements; gabapentin – which lessens the frequency and severity of hot flashes; fezolinetant (Veozah), a novel first-in-class neurokinin B antagonist that was Food and Drug Administration–approved in May for VSM; and oxybutynin, an antimuscarinic, anticholinergic drug, that reduces moderate to severe VMS, although long-term use in older adults may be linked to cognitive decline, weight loss, and stellate ganglion block.

Therapies that were ineffective, associated with adverse effects (AEs), or lacking adequate evidence of efficacy and thus not recommended for VMS included: paced respiration; supplemental and herbal remedies such as black cohosh, milk thistle, and evening primrose; cooling techniques; trigger avoidance; exercise and yoga; mindfulness-based intervention and relaxation; suvorexant, a dual orexin-receptor antagonist used for insomnia; soy foods, extracts, and the soy metabolite equol; cannabinoids; acupuncture; calibration of neural oscillations; chiropractics; clonidine, an alpha-2 adrenergic agonist that is associated with significant AEs with no recent evidence of benefit over placebo; dietary modification; and pregabalin – which is associated with significant AEs and has controlled-substance prescribing restrictions.

Ultimately, clinicians should individualize menopause care to each patient. For example, “if a patient says that avoiding caffeine in the morning stops her from having hot flashes in the afternoon, that’s fine,” Dr. Shufelt said.
 

HT still most effective

“This statement is excellent, comprehensive, and evidence-based,” commented Jill M. Rabin MD, vice chair of education and development, obstetrics and gynecology, at Northshore University Hospital/LIJ Medical Center in Manhasset, N.Y., and professor of obstetrics and gynecology at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health in Hempstead, N.Y.

Dr. Rabin, coauthor of Mind Over Bladder was not involved in compiling the statement.

She agreed that hormone therapy is the most effective option for VMS and regularly prescribes it for suitable candidates in different forms depending on the type and severity of menopausal symptoms. As for nonhormonal options, Dr. Rabin added in an interview, some of those not recommended in the current NAMS statement could yet prove to be effective as more data accumulate. Suvorexant may be one to watch, for instance, but currently there are not enough data on its effectiveness.

“It’s really important to keep up on this nonhormonal research,” Dr. Rabin said. “As the population ages, more and more women will be in the peri- and postmenopausal periods and some have medical reasons for not taking hormone therapy.” It’s important to recommend nonhormonal therapies of proven benefit according to current high-level evidence, she said, “but also to keep your ear to the ground about those still under investigation.”

As for the lifestyle and alternative remedies of unproven benefit, Dr. Rabin added, there’s little harm in trying them. “As far as I know, no one’s ever died of relaxation and paced breathing.” In addition, a patient’s interaction with and sense of control over her own physiology provided by these techniques may be beneficial in themselves.

Dr. Shufelt reported grant support from the National Institutes of Health. Numerous authors reported consulting fees from and other financial ties to private-sector companies. Dr. Rabin had no relevant competing interests to disclose with regard to her comments.

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

Researchers using a modeling study of rabies in the United States have quantified the risk of death and exposure and estimated a threshold to help health care providers decide when postexposure prophylaxis (PEP) is appropriate.

© astridb05/Fotolia.com

The model, reported in JAMA Network Open, could help clinicians, particularly those in primary care settings, to more rationally prescribe PEP to people concerned about a potential exposure to the rabies virus (RABV). In the United States, rabies PEP often is given without a comprehensive assessment that considers regional factors as well as species, nature of an attack, and the health and vaccination status of the animal.

Providers err on the side of caution, as rabies infection has a fatality rate near 100%. When exposures are low-risk, however, patients can rack up substantial out-of-pocket expenses or experience unnecessary adverse effects from the series of shots. Those can include injection site reactions, hypersensitivity reactions, and neurological complications.

The authors write that an estimated 55,000 people per year in the United States were treated for potential exposure to RABV in 2017 and 2018, at an estimated cost of more than $3,800 per person treated.
 

Researchers calculate risk threshold

The researchers, led by Kelly Charniga, PhD, MPH, an infectious disease epidemiologist with the U.S. Centers for Disease Control and Prevention in Atlanta, calculated positivity rates using more than 900,000 animal samples tested for RABV between 2011 and 2020. Other parameters were estimated from surveillance data and the literature and probabilities were estimated using Bayes’ rule.

A convenience sample of state public health officials in all states (excluding Hawaii) plus Washington and Puerto Rico was used to help determine a risk threshold for recommending PEP. Respondents were asked whether they would recommend PEP given 24 standardized exposure scenarios while accounting for local rabies epidemiology.

Their model establishes a risk threshold of 0.0004 for PEP administration, which represents the probability that an animal would test positive for RABV given that a person was exposed, and the probability that a person would die from rabies after exposure to a suspect rabid animal and no PEP. PEP should not be recommended with any value lower than that cutoff.

Alfred DeMaria, DPH, a consultant to the Massachusetts Department of Public Health in Boston, who was not involved with the study, said the work will be particularly helpful for primary care physicians, giving them confidence to not recommend PEP when infection is statistically highly unlikely and thereby to reduce unnecessary and costly measures.

“Concern about rabies is often based on a very unlikely scenario,” Dr. DeMaria said. He gave the example of people coming into primary care worried that they might have been exposed after comforting their dog who had been bitten in a fight with a wild animal.

“Has that ever happened in the history of the human species? Not that we know of,” he said.

Many people also think dogs and other domestic animals are a likely source of rabies, which is not the case in the United States, Dr. DeMaria said.

“In most cases, it is exposure to a raccoon, a skunk, or a bat,” he said. “Most calls are for potential bat exposure, especially in the summer when young bats are flying around and are not very savvy about avoiding humans.”

The authors note the difference between the animals likely to bite and the species that carry RABV: “The most common mammals involved in bite events in the U.S. are dogs, cats, and small rodents. These species, when healthy and provoked into biting, represent some of the lowest risk exposures evaluated in this model.”

The canine rabies variant virus was eliminated in the United States in 2004.

The study authors note that their model should not be used in other countries because “most rabies deaths globally are caused by domestic dogs.”

Health department consultation can reduce inappropriate treatment

Dr. DeMaria said the paper may also convince physicians to consult with their health department for a final recommendation.

The authors note that a 2020 study in Cook County, Ill., found patients who received PEP were about 90% less likely to receive inappropriate treatment if their clinician had consulted with a health department.

“Anything that puts the risk in a context, like this paper does, is helpful,” he said.

Most physicians in the United States will never see a patient with rabies, the authors write, but animal bites are common – resulting in hundreds of thousands of primary care and emergency department visits each year when physicians must decide whether to administer PEP.

The study authors and Dr. DeMaria report no relevant financial relationships.

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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

MUNICH, GERMANY – Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.

The research, presented at the annual European Stroke Organisation Conference, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk versus standard treatment.

The study involved more than 6,000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive versus standard antiplatelet therapy and intensive statin therapy within 24 hours versus waiting up to 72 hours after onset.

Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% versus standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.

Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome versus waiting up to 72 hours by 16%.

Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, department of neurology, Beijing Tiantan Hospital, National Clinical Research Center.

There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.

Approached for comment, session cochair Carlos Molina, MD, director of the stroke unit and brain hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”

He said in an interview that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated ... in particular with reductions in disabling stoke, and that’s good.”
 

Recurrence and progression

Dr. Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often caused by ICAS/ECAS.

Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.

In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.

Dr. Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.

To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.

The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including nonstenotic vulnerable plaques.

Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.

TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.

Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.

Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:

• Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
• Intensive antiplatelet therapy plus delayed high-intensity statin therapy
• Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
• Standard antiplatelet therapy plus delayed high-intensity statin therapy

In all, 6,100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.

The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases versus 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.

The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive versus standard antiplatelet therapy, at a cumulative probability of 9.2% versus 7.3% (hazard ratio, 0.79; 95% confidence interval, 0.66-0.94; P = .007).

Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death versus aspirin alone, at 7.5% versus 9.3% (HR, 0.80; 95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).

The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% versus 0.4% for aspirin alone (HR, 2.08; 95% CI, 1.07-4.03; P = .02).

Turning to statin use, Dr. Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% versus 8.1% (HR, 0.95; P = .58).

There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate versus 0.6% for delayed intensive statin therapy (HR, 1.36; 95% CI, 0.73-2.54; P = .34).

Dr. Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.

Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate versus delayed statin therapy (odds ratio, 0.84; 95% CI, 0.72-0.99; P = .04).

Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding versus delayed statin therapy, affecting 1.1% versus 0.7% of patients. The association nonetheless did not reach statistical significance (HR, 1.70; 95% CI, 0.78-3.71; P = .18).

The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships were declared.

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