A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.

A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.

A trastuzumab biosimilar drug has shown an equivalent response, compared with trastuzumab, in the treatment of ERBB2 (HER2)-positive metastatic breast cancer, according to the results of a randomized double-blind controlled trial.

The anti-ERBB2 humanized monoclonal antibody trastuzumab in combination with chemotherapy has been found in numerous trials to significantly improve progression-free survival and overall survival in women with ERBB2-positive metastatic breast, compared with chemotherapy alone.

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Ferric citrate was safe and effective for treatment of iron-deficiency anemia in patients who had non–dialysis-dependent chronic kidney disease (NDD-CKD), based on data from a phase III, randomized, double-blind study.

The responses were durable, and none of the patients received erythropoiesis-stimulating agents (ESAs), presenter Pablo Pergola, MD, PhD, of Renal Associates, San Antonio, said in an interview at a meeting sponsored by the American Society of Nephrology.

Brian Hoyle/Frontline Medical News

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

Papular Mucinosis/Scleromyxedema

Papular mucinosis/scleromyxedema, also known as generalized lichen myxedematosus, is a rare dermal mucinosis characterized by a papular eruption that can have an associated IgG λ paraproteinemia. The clinical presentation is gradual with the development of firm, flesh-colored, 2- to 3-mm papules often involving the hands, face, and neck that can progress to plaques that cover the entire body. Skin stiffening also can be seen.¹ Extracutaneous symptoms are common and include dysphagia, arthralgia, myopathy, and cardiac dysfunction.² Occasionally, central nervous system involvement can lead to the often fatal dermato-neuro syndrome.^3,4

Histologically, papular mucinosis/scleromyxedema demonstrates increased, irregularly arranged fibroblasts in the reticular dermis with increased dermal mucin deposition (quiz image and Figure 1). The epidermis is normal or slightly thinned due to pressure from dermal changes. There may be a mild superficial perivascular lymphocytic infiltrate and atrophy of hair follicles.5 In this case, the clinical and histologic findings best supported a diagnosis of papular mucinosis/scleromyxedema.

Infundibulofolliculitis is a pruritic follicular papular eruption typically involving the neck, trunk, and proximal upper arms and shoulders. It is most common in black men who reside in hot and humid climates. Although infundibulofolliculitis would be included in the clinical differential diagnosis for the current patient, the histopathologic findings were quite distinct for the correct diagnosis of papular mucinosis/scleromyxedema. Infundibulofolliculitis shows widening of the upper part of the hair follicle (infundibulum) and infundibular inflammatory infiltrate with follicular spongiosis (Figure 2). Neither mucin deposition nor fibroblast proliferation is appreciated in infundibulofolliculitis.^6,7 

Granuloma annulare (GA) often can be distinguished clinically from papular mucinosis/scleromyxedema due to the annular appearance of papules and plaques in GA and the lack of stiffness of underlying skin. Interstitial granuloma annulare is a histologic variant of GA that can be included in the histologic differential diagnosis of papular mucinosis/scleromyxedema. Histologically, there is an interstitial infiltrate of cytologically bland histiocytes dissecting between collagen bundles in interstitial GA (Figure 3). Necrobiosis and collections of mucin often are inconspicuous. Occasionally, the presence of eosinophils can be a helpful clue.⁸ A fibroblast proliferation is not a feature of GA.

Reticular erythematous mucinosis also is a type of cutaneous mucinosis but with a classic clinical appearance of a reticulated erythematous plaque on the chest or back, making it clinically distinct from papular mucinosis/scleromyxedema and the presentation described in the current patient. Reticular erythematous mucinosis can be histologically distinguished from papular mucinosis/scleromyxedema by the presence of a superficial and deep perivascular lymphocytic infiltrate with increased dermal mucin deposition (Figure 4). It often shows a positive IgM deposition on the basement membrane on direct immunofluorescence.⁹

Similar to papular mucinosis/scleromyxedema, scleredema shows thickening of the skin with decreased movement of involved areas. Scleredema often involves the upper back, shoulders, and neck where affected areas often have a peau d'orange appearance. Scleredema is classified into 3 clinical forms based on clinical associations. Type 1 often is preceded by an infection, classically Streptococcus pyogenes. Type 2 is associated with a hematologic dyscrasia such as multiple myeloma, or it can have an associated paraproteinemia that is typically of the IgA κ type, which is distinct from papular mucinosis/scleromyxedema where IgG λ paraproteinemia typically is seen. Type 3 is associated with diabetes mellitus. Histologically, scleredema also is distinct from papular mucinosis/scleromyxedema. Although increased mucin is seen in the dermis, the mucin is classically more prominent in the deep reticular dermis as compared with papular mucinosis/scleromyxedema (Figure 5). Additionally, collagen bundles are thickened with clear separation between them. Hyperplasia of fibroblasts in the dermis that is a characteristic feature of papular mucinosis/scleromyxedema is not observed in scleredema.¹⁰

SAN FRANCISCO – More than two-thirds of parents worry about their children’s privacy online and/or that photos of their children might be reshared on the wider Web, according to a survey conducted by C.S. Mott Children’s Hospital.

Those fears are not baseless, and they need to be considered more often by parents themselves in posting about their children online, presenters agreed at a symposium on the media at the annual meeting of the American Academy of Pediatrics.

“The first children of social media are just now entering adulthood, entering the job market,” said Stacey Steinberg, JD, a legal skills professor at the University of Florida Levin College of Law, Gainesville. She is also with the law school’s center on children and families.

She and Bahareh Keith, DO, a pediatrician at the University of Florida, discussed the challenges and risks of “sharenting” – parents’ sharing information and photos of their children online – and pediatricians’ role in advising parents and looking out for children’s best interests.

“The dearth of discussion on this topic leaves even the most well-intentioned parents without enough information to thoroughly analyze this,” Ms. Steinberg said. “We’re not sitting here saying we know what the answers are. But we’re saying this is an important issue that affects families, and these children require a voice in this discussion.”

The way social media and blogging have changed the landscape for children coming of age today means that they often have a digital footprint shaped by their parents long before they create their own first account. This reality means it’s necessary to consider how to balance children’s right to privacy with parents’ right to free speech and expression.

The 2015 C.S. Mott survey asked 569 parents of children aged 4 years and younger about how they use social media as parents, and reported that more than half of mothers (56%) and a third of fathers (34%) discuss parenting and child health topics on Facebook, Twitter, blogs, online forums, and other online platforms.

The risks of this sharenting can range from embarrassment of the child to significantly more sinister repercussions. Just over half of the parents (52%) in the Mott survey reported that they are concerned their child might feel embarrassed when they grow older and discover what their parents shared online. But that embarrassment also can lead to bullying or determent of psychosocial development, Ms. Steinberg and Dr. Keith explained.

More serious, if less common, risks include the possibility that data brokers could access and use information about the children or that online child pornographers could repurpose the photos inappropriately. One worst case scenario of the former is digital kidnapping, a disturbing practice in which a stranger uses baby photos and information that is not their own to pass off the child as their own or to invite others to “invent” identities for the child. The Children’s Online Privacy Protection Rule of the Federal Trade Commission addresses only online use by those under age 13 years, not others’ use of those images.

Regarding the latter, Ms. Steinberg and Dr. Keith showed an example of a bare-bottomed baby standing in front of a bathtub that had been reshared hundreds of times, but other images that have been shared on child pornography sites depict children in everyday situations such as playing on a playground, running at the beach, or doing gymnastics.

“These are images that many of us would think are innocent, but pornographers would categorize these into folders,” Dr. Keith said. “It’s not even naked or half-naked pictures.”

A study conducted by an e-safety commission in Australia, for example, found that half of the thousands of photos shared on a sample of child pornography sites had originated from parental sharing.

But Ms. Steinberg and Dr. Keith pointed out that benefits of parents’ online sharing exist as well, as the Mott survey found. In that survey, 72% of parents who discuss parenting and/or their children on social media reported that doing so helps them feel less alone. Similarly, 70% said they learn what not to do through those experiences, 67% said they receive advice from more experienced parents, and 62% said they consequently worry less. Common topics they discussed included sleep, nutrition, discipline, day care, and behavior management.

Other benefits, Ms. Steinberg pointed out, are that families geographically spread apart can stay connected, and communities can grow stronger with shared communal experiences of parents meeting others online.

“For some parents, it gives them an opportunity for advocacy work and raises awareness for important social issues,” Ms. Steinberg said, although she added, “If you’re going to share your children’s behavioral problems, consider sharing anonymously.”

Neither Ms. Steinberg and Dr. Keith said they had simple solutions to these challenges. Rather, they recommended using the public health model of raising awareness and encouraging open dialogue among pediatricians, parents, and their children to look for ways to balance competing interests.

“Social media offers many positive benefits, and we don’t want to silence the many voices of parents who take part in online sharing,” Ms. Steinberg explained. But she and Ms. Keith said it’s also worth considering children’s potential interest in controlling what their digital footprint is as they become adults.

For example, one study they cited found that, among 249 pairs of parents and their children, three times more children than parents wanted the parents to have and follow rules regarding what they could share on social media about their children.

Although guidance for parents on monitoring children’s social media use is a part of the AAP policy statement on media, only one recommendation obliquely addresses how parents should or shouldn’t use social media by advising them to model appropriate use for their children.

“It’s just like any medical decision: What is the benefit, and what is the risk, and does the benefit outweigh the risk?” said Wendy Sue Swanson, MD, executive director of digital health at Seattle Children’s Hospital. She recommended that parents ask their child for permission before posting a story or photo if their kids are aged 6 or older.

Ms. Steinberg and Dr. Keith recommended that pediatricians broach this subject with parents to help them think about risks they simply might not have considered before.

“When we looked at what sorts of best practices could be encouraged or doctors could talk to parents about – the tangible harms, such as whether data brokers or people interested in child pornography could access the information – we didn’t want to create any unnecessary panic,” Ms. Steinberg said. “But we did find some concerns that were troublesome, and we thought that parents or at least physicians [should] be aware of those potential risks.”

Ms. Steinberg and Dr. Keith reported that they had no relevant financial disclosures.

SAN FRANCISCO – More than two-thirds of parents worry about their children’s privacy online and/or that photos of their children might be reshared on the wider Web, according to a survey conducted by C.S. Mott Children’s Hospital.

Those fears are not baseless, and they need to be considered more often by parents themselves in posting about their children online, presenters agreed at a symposium on the media at the annual meeting of the American Academy of Pediatrics.

“The first children of social media are just now entering adulthood, entering the job market,” said Stacey Steinberg, JD, a legal skills professor at the University of Florida Levin College of Law, Gainesville. She is also with the law school’s center on children and families.

She and Bahareh Keith, DO, a pediatrician at the University of Florida, discussed the challenges and risks of “sharenting” – parents’ sharing information and photos of their children online – and pediatricians’ role in advising parents and looking out for children’s best interests.

“The dearth of discussion on this topic leaves even the most well-intentioned parents without enough information to thoroughly analyze this,” Ms. Steinberg said. “We’re not sitting here saying we know what the answers are. But we’re saying this is an important issue that affects families, and these children require a voice in this discussion.”

The way social media and blogging have changed the landscape for children coming of age today means that they often have a digital footprint shaped by their parents long before they create their own first account. This reality means it’s necessary to consider how to balance children’s right to privacy with parents’ right to free speech and expression.

The 2015 C.S. Mott survey asked 569 parents of children aged 4 years and younger about how they use social media as parents, and reported that more than half of mothers (56%) and a third of fathers (34%) discuss parenting and child health topics on Facebook, Twitter, blogs, online forums, and other online platforms.

The risks of this sharenting can range from embarrassment of the child to significantly more sinister repercussions. Just over half of the parents (52%) in the Mott survey reported that they are concerned their child might feel embarrassed when they grow older and discover what their parents shared online. But that embarrassment also can lead to bullying or determent of psychosocial development, Ms. Steinberg and Dr. Keith explained.

More serious, if less common, risks include the possibility that data brokers could access and use information about the children or that online child pornographers could repurpose the photos inappropriately. One worst case scenario of the former is digital kidnapping, a disturbing practice in which a stranger uses baby photos and information that is not their own to pass off the child as their own or to invite others to “invent” identities for the child. The Children’s Online Privacy Protection Rule of the Federal Trade Commission addresses only online use by those under age 13 years, not others’ use of those images.

Regarding the latter, Ms. Steinberg and Dr. Keith showed an example of a bare-bottomed baby standing in front of a bathtub that had been reshared hundreds of times, but other images that have been shared on child pornography sites depict children in everyday situations such as playing on a playground, running at the beach, or doing gymnastics.

“These are images that many of us would think are innocent, but pornographers would categorize these into folders,” Dr. Keith said. “It’s not even naked or half-naked pictures.”

A study conducted by an e-safety commission in Australia, for example, found that half of the thousands of photos shared on a sample of child pornography sites had originated from parental sharing.

But Ms. Steinberg and Dr. Keith pointed out that benefits of parents’ online sharing exist as well, as the Mott survey found. In that survey, 72% of parents who discuss parenting and/or their children on social media reported that doing so helps them feel less alone. Similarly, 70% said they learn what not to do through those experiences, 67% said they receive advice from more experienced parents, and 62% said they consequently worry less. Common topics they discussed included sleep, nutrition, discipline, day care, and behavior management.

Other benefits, Ms. Steinberg pointed out, are that families geographically spread apart can stay connected, and communities can grow stronger with shared communal experiences of parents meeting others online.

“For some parents, it gives them an opportunity for advocacy work and raises awareness for important social issues,” Ms. Steinberg said, although she added, “If you’re going to share your children’s behavioral problems, consider sharing anonymously.”

Neither Ms. Steinberg and Dr. Keith said they had simple solutions to these challenges. Rather, they recommended using the public health model of raising awareness and encouraging open dialogue among pediatricians, parents, and their children to look for ways to balance competing interests.

“Social media offers many positive benefits, and we don’t want to silence the many voices of parents who take part in online sharing,” Ms. Steinberg explained. But she and Ms. Keith said it’s also worth considering children’s potential interest in controlling what their digital footprint is as they become adults.

For example, one study they cited found that, among 249 pairs of parents and their children, three times more children than parents wanted the parents to have and follow rules regarding what they could share on social media about their children.

Although guidance for parents on monitoring children’s social media use is a part of the AAP policy statement on media, only one recommendation obliquely addresses how parents should or shouldn’t use social media by advising them to model appropriate use for their children.

“It’s just like any medical decision: What is the benefit, and what is the risk, and does the benefit outweigh the risk?” said Wendy Sue Swanson, MD, executive director of digital health at Seattle Children’s Hospital. She recommended that parents ask their child for permission before posting a story or photo if their kids are aged 6 or older.

Ms. Steinberg and Dr. Keith recommended that pediatricians broach this subject with parents to help them think about risks they simply might not have considered before.

“When we looked at what sorts of best practices could be encouraged or doctors could talk to parents about – the tangible harms, such as whether data brokers or people interested in child pornography could access the information – we didn’t want to create any unnecessary panic,” Ms. Steinberg said. “But we did find some concerns that were troublesome, and we thought that parents or at least physicians [should] be aware of those potential risks.”

Ms. Steinberg and Dr. Keith reported that they had no relevant financial disclosures.

SAN FRANCISCO – More than two-thirds of parents worry about their children’s privacy online and/or that photos of their children might be reshared on the wider Web, according to a survey conducted by C.S. Mott Children’s Hospital.

Those fears are not baseless, and they need to be considered more often by parents themselves in posting about their children online, presenters agreed at a symposium on the media at the annual meeting of the American Academy of Pediatrics.

“The first children of social media are just now entering adulthood, entering the job market,” said Stacey Steinberg, JD, a legal skills professor at the University of Florida Levin College of Law, Gainesville. She is also with the law school’s center on children and families.

She and Bahareh Keith, DO, a pediatrician at the University of Florida, discussed the challenges and risks of “sharenting” – parents’ sharing information and photos of their children online – and pediatricians’ role in advising parents and looking out for children’s best interests.

“The dearth of discussion on this topic leaves even the most well-intentioned parents without enough information to thoroughly analyze this,” Ms. Steinberg said. “We’re not sitting here saying we know what the answers are. But we’re saying this is an important issue that affects families, and these children require a voice in this discussion.”

The way social media and blogging have changed the landscape for children coming of age today means that they often have a digital footprint shaped by their parents long before they create their own first account. This reality means it’s necessary to consider how to balance children’s right to privacy with parents’ right to free speech and expression.

The 2015 C.S. Mott survey asked 569 parents of children aged 4 years and younger about how they use social media as parents, and reported that more than half of mothers (56%) and a third of fathers (34%) discuss parenting and child health topics on Facebook, Twitter, blogs, online forums, and other online platforms.

The risks of this sharenting can range from embarrassment of the child to significantly more sinister repercussions. Just over half of the parents (52%) in the Mott survey reported that they are concerned their child might feel embarrassed when they grow older and discover what their parents shared online. But that embarrassment also can lead to bullying or determent of psychosocial development, Ms. Steinberg and Dr. Keith explained.

More serious, if less common, risks include the possibility that data brokers could access and use information about the children or that online child pornographers could repurpose the photos inappropriately. One worst case scenario of the former is digital kidnapping, a disturbing practice in which a stranger uses baby photos and information that is not their own to pass off the child as their own or to invite others to “invent” identities for the child. The Children’s Online Privacy Protection Rule of the Federal Trade Commission addresses only online use by those under age 13 years, not others’ use of those images.

Regarding the latter, Ms. Steinberg and Dr. Keith showed an example of a bare-bottomed baby standing in front of a bathtub that had been reshared hundreds of times, but other images that have been shared on child pornography sites depict children in everyday situations such as playing on a playground, running at the beach, or doing gymnastics.

“These are images that many of us would think are innocent, but pornographers would categorize these into folders,” Dr. Keith said. “It’s not even naked or half-naked pictures.”

A study conducted by an e-safety commission in Australia, for example, found that half of the thousands of photos shared on a sample of child pornography sites had originated from parental sharing.

But Ms. Steinberg and Dr. Keith pointed out that benefits of parents’ online sharing exist as well, as the Mott survey found. In that survey, 72% of parents who discuss parenting and/or their children on social media reported that doing so helps them feel less alone. Similarly, 70% said they learn what not to do through those experiences, 67% said they receive advice from more experienced parents, and 62% said they consequently worry less. Common topics they discussed included sleep, nutrition, discipline, day care, and behavior management.

Other benefits, Ms. Steinberg pointed out, are that families geographically spread apart can stay connected, and communities can grow stronger with shared communal experiences of parents meeting others online.

“For some parents, it gives them an opportunity for advocacy work and raises awareness for important social issues,” Ms. Steinberg said, although she added, “If you’re going to share your children’s behavioral problems, consider sharing anonymously.”

Neither Ms. Steinberg and Dr. Keith said they had simple solutions to these challenges. Rather, they recommended using the public health model of raising awareness and encouraging open dialogue among pediatricians, parents, and their children to look for ways to balance competing interests.

“Social media offers many positive benefits, and we don’t want to silence the many voices of parents who take part in online sharing,” Ms. Steinberg explained. But she and Ms. Keith said it’s also worth considering children’s potential interest in controlling what their digital footprint is as they become adults.

For example, one study they cited found that, among 249 pairs of parents and their children, three times more children than parents wanted the parents to have and follow rules regarding what they could share on social media about their children.

Although guidance for parents on monitoring children’s social media use is a part of the AAP policy statement on media, only one recommendation obliquely addresses how parents should or shouldn’t use social media by advising them to model appropriate use for their children.

“It’s just like any medical decision: What is the benefit, and what is the risk, and does the benefit outweigh the risk?” said Wendy Sue Swanson, MD, executive director of digital health at Seattle Children’s Hospital. She recommended that parents ask their child for permission before posting a story or photo if their kids are aged 6 or older.

Ms. Steinberg and Dr. Keith recommended that pediatricians broach this subject with parents to help them think about risks they simply might not have considered before.

“When we looked at what sorts of best practices could be encouraged or doctors could talk to parents about – the tangible harms, such as whether data brokers or people interested in child pornography could access the information – we didn’t want to create any unnecessary panic,” Ms. Steinberg said. “But we did find some concerns that were troublesome, and we thought that parents or at least physicians [should] be aware of those potential risks.”

Ms. Steinberg and Dr. Keith reported that they had no relevant financial disclosures.

Oncology Practice associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar reveal several anticipated studies from the 39th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 7:

• S1-02. PrECOG 0102. A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer resistant to aromatase inhibitor therapy

• S1-03. First results from the multicenter phase III DATA study comparing 3 vs. 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with HR–positive early breast cancer.

• S1-04. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05).

• S1-05. A randomized, double-blind, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with HR–positive breast cancer who have completed previous adjuvant endocrine therapy: initial results of NRG oncology/NSABP B-42.

• S1-08. Prognostic associations of tumor-infiltrating lymphocytes in metastatic HER2-positive breast cancer treated with trastuzumab and pertuzumab: a secondary analysis of the CLEOPATRA study.

• S3-01.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and deputy chief in the division of hematology/oncology, Feinberg School of Medicine, Chicago; and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

Oncology Practice associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar reveal several anticipated studies from the 39th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 7:

• S1-02. PrECOG 0102. A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer resistant to aromatase inhibitor therapy

• S1-03. First results from the multicenter phase III DATA study comparing 3 vs. 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with HR–positive early breast cancer.

• S1-04. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05).

• S1-05. A randomized, double-blind, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with HR–positive breast cancer who have completed previous adjuvant endocrine therapy: initial results of NRG oncology/NSABP B-42.

• S1-08. Prognostic associations of tumor-infiltrating lymphocytes in metastatic HER2-positive breast cancer treated with trastuzumab and pertuzumab: a secondary analysis of the CLEOPATRA study.

• S3-01.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and deputy chief in the division of hematology/oncology, Feinberg School of Medicine, Chicago; and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

Oncology Practice associate editors Dr. Hope S. Rugo and Dr. William J. Gradishar reveal several anticipated studies from the 39th annual San Antonio Breast Cancer Symposium, set to begin on Wednesday, Dec. 7:

• S1-02. PrECOG 0102. A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer resistant to aromatase inhibitor therapy

• S1-03. First results from the multicenter phase III DATA study comparing 3 vs. 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with HR–positive early breast cancer.

• S1-04. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05).

• S1-05. A randomized, double-blind, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with HR–positive breast cancer who have completed previous adjuvant endocrine therapy: initial results of NRG oncology/NSABP B-42.

• S1-08. Prognostic associations of tumor-infiltrating lymphocytes in metastatic HER2-positive breast cancer treated with trastuzumab and pertuzumab: a secondary analysis of the CLEOPATRA study.

• S3-01.

Dr. Rugo is professor of medicine, University of California, San Francisco, and director, breast oncology and clinical trials education, UCSF Helen Diller Family Comprehensive Cancer Center. Dr. Gradishar is the Betsy Bramsen Professor of Breast Oncology, professor of medicine, and deputy chief in the division of hematology/oncology, Feinberg School of Medicine, Chicago; and deputy director for the Clinical Network and director of the Maggie Daley Center for Women’s Cancer Care, Robert H. Lurie Comprehensive Cancer Center Network of Northwestern University, Chicago.

The diagnosis

To clarify the diagnosis, endoscopic resection of the smaller lesion was performed and deeper biopsies of the other lesions were taken. Histology revealed lymphoid, centroblast, and centrocyte-like cell proliferation with follicular pattern (Figure D). Immunohistochemically, the follicles stained for bcl-6, CD20, and bcl-2 (Figure E), but not CD3, CD5, CD10, or cyclin D1.

Malignant lymphomas of the colon represent about 0.2% of all colonic neoplasms and most frequently are diffuse large B-cell, mucosa-associated lymphoid tissue, and mantle cell lymphomas.2 This phenotypic presentation, as multiple lymphomatous polyposis, has been reported in colon follicular lymphomas but is more typical of mantle cell lymphoma.3 Treatment usually consists of chemotherapy containing rituximab (anti-CD20) and should be decided on a case-by-case basis owing to possible relapse and the often indolent course.1

References

1. Damaj, G., Verkarre, V., Delmer, A. et al. Primary follicular lymphoma of the gastrointestinal tract: A study of 25 cases and a literature review. Ann Oncol. 2003;14:623-9.

2. Muller-Hermelink, H.K., Chott, A., Gascoyne, R.D. et al. B-cell lymphoma of the colon and rectum. In: S.R. Hamilton, L.A. Asltonen, eds. WHO Classification of Tumours. Lyon, France: IARC Press;2001:139-41.

3. Hiraide, T., Shoji, T., Higashi, Y. et al. Extranodal multiple polypoid follicular lymphoma of the sigmoid colon. Gastrointest Endosc. 2011;73(1):182-4.

The diagnosis

To clarify the diagnosis, endoscopic resection of the smaller lesion was performed and deeper biopsies of the other lesions were taken. Histology revealed lymphoid, centroblast, and centrocyte-like cell proliferation with follicular pattern (Figure D). Immunohistochemically, the follicles stained for bcl-6, CD20, and bcl-2 (Figure E), but not CD3, CD5, CD10, or cyclin D1.

Malignant lymphomas of the colon represent about 0.2% of all colonic neoplasms and most frequently are diffuse large B-cell, mucosa-associated lymphoid tissue, and mantle cell lymphomas.2 This phenotypic presentation, as multiple lymphomatous polyposis, has been reported in colon follicular lymphomas but is more typical of mantle cell lymphoma.3 Treatment usually consists of chemotherapy containing rituximab (anti-CD20) and should be decided on a case-by-case basis owing to possible relapse and the often indolent course.1

References

1. Damaj, G., Verkarre, V., Delmer, A. et al. Primary follicular lymphoma of the gastrointestinal tract: A study of 25 cases and a literature review. Ann Oncol. 2003;14:623-9.

2. Muller-Hermelink, H.K., Chott, A., Gascoyne, R.D. et al. B-cell lymphoma of the colon and rectum. In: S.R. Hamilton, L.A. Asltonen, eds. WHO Classification of Tumours. Lyon, France: IARC Press;2001:139-41.

3. Hiraide, T., Shoji, T., Higashi, Y. et al. Extranodal multiple polypoid follicular lymphoma of the sigmoid colon. Gastrointest Endosc. 2011;73(1):182-4.

The diagnosis

To clarify the diagnosis, endoscopic resection of the smaller lesion was performed and deeper biopsies of the other lesions were taken. Histology revealed lymphoid, centroblast, and centrocyte-like cell proliferation with follicular pattern (Figure D). Immunohistochemically, the follicles stained for bcl-6, CD20, and bcl-2 (Figure E), but not CD3, CD5, CD10, or cyclin D1.

Malignant lymphomas of the colon represent about 0.2% of all colonic neoplasms and most frequently are diffuse large B-cell, mucosa-associated lymphoid tissue, and mantle cell lymphomas.2 This phenotypic presentation, as multiple lymphomatous polyposis, has been reported in colon follicular lymphomas but is more typical of mantle cell lymphoma.3 Treatment usually consists of chemotherapy containing rituximab (anti-CD20) and should be decided on a case-by-case basis owing to possible relapse and the often indolent course.1

References

1. Damaj, G., Verkarre, V., Delmer, A. et al. Primary follicular lymphoma of the gastrointestinal tract: A study of 25 cases and a literature review. Ann Oncol. 2003;14:623-9.

2. Muller-Hermelink, H.K., Chott, A., Gascoyne, R.D. et al. B-cell lymphoma of the colon and rectum. In: S.R. Hamilton, L.A. Asltonen, eds. WHO Classification of Tumours. Lyon, France: IARC Press;2001:139-41.

3. Hiraide, T., Shoji, T., Higashi, Y. et al. Extranodal multiple polypoid follicular lymphoma of the sigmoid colon. Gastrointest Endosc. 2011;73(1):182-4.

Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Total knee arthroplasty (TKA) is an efficacious procedure for end-stage knee arthritis. Although TKA is cost-effective and has a high rate of success,^1-6 TKAs fail and may require revision surgery. Failure mechanisms include periprosthetic fracture, aseptic loosening, wear, osteolysis, instability, and infection.^7-9 In these cases, revision arthroplasty may be needed in order to restore function.

There has been a steady increase in the number of primary and revision TKAs performed in the United States.^8,10,11 Revision rates are 4% at 5 years after index TKA and 8.9% at 9 years.¹² However, surgical techniques and improved implants have led to improved outcomes after primary TKA, as evidenced by the reduction in revisions performed for polyethylene wear and osteolysis.¹³ Given the continuing need for revision TKAs (despite technical improvements¹³), evidence-based standard protocols that improve outcomes after revision TKA are necessary.

The Total Joint Replacement Perioperative Surgical Home (TJR-PSH) implemented and used by surgeons and anesthesiologists at our institution has shown that an evidence-based perioperative protocol can provide consistent and improved outcomes in primary TKA.^14-16

Materials and Methods

In this study, which received Institutional Review Board approval, we performed a prospective cross-sectional analysis comparing the perioperative outcomes of patients who underwent primary TKA with those of patients who underwent revision TKA. Medical records and our institution’s data registry were queried for LOS, discharge disposition, readmission rates, and reoperation rates.

The study included all primary and revision TKAs performed at our institution since the inception of TJA-PSH. Unicompartmental knee arthroplasties and exchanges of a single component (patella, tibia, or femur) were excluded. We identified a total of 285 consecutive primary or revision TKAs, all performed by a single surgeon. Three cases lacked complete data and were excluded, leaving 282 cases: 235 primary and 50 revision TKAs (no simultaneous bilateral TKAs). The demographic data we collected included age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, calculated Charlson Comorbidity Index (CCI), LOS, and discharge disposition.

The same established perioperative surgical home clinical pathway was used to care for all patients, whether they underwent primary or revision TKA. The primary outcomes studied were LOS, discharge disposition (subacute nursing facility or home), 30-day orthopedic readmission, and return to operating room. All reoperations on the same knee were analyzed.

Statistical Analysis

Primary and revision TKAs were compared on LOS (with an independent-sample t test) and discharge disposition, 30-day readmissions, and reoperations (χ² Fisher exact test). Multivariate regression analysis was performed with each primary outcome, using age, sex, BMI, ASA score, and CCI as covariates. Statistical significance was set at P ≤ .05. All analyses were performed with SPSS Version 16.0 (SPSS Inc.) and Microsoft Excel 2011 (Microsoft).

Results

Mean (SD) age was 66 (13.2) years for primary TKA patients and 62 (12.8) years for revision TKA patients. The cohort had more women (62.5%) than men (37.5%). There was no statistical difference in patient demographics with respect to age (P = .169) or BMI (P = .701) between the 2 groups. There was an even age distribution within each group and between the groups (Table).

There was no statistically significant difference in LOS between the groups. Mean (SD) LOS was 2.55 (1.25) days for primary TKA and 2.92 (1.24) days for revision TKA (P = .061; 95% confidence interval [CI], 0.017-0.749). Regression analysis showed a correlation between ASA score and LOS for primary TKAs but not revision TKAs. For every unit increase in ASA score, there was a 0.39-day increase in LOS for primary TKA (P = .46; 95% CI, 0.006-0.781). There was no correlation between ASA score and LOS for revision TKA when controlling for covariates (P = .124). Eighty (34%) of the 235 primary TKA patients and 21 (41%) of the 50 revision TKA patients were discharged to a subacute nursing facility; the difference was not significant (P = .123). No patient was discharged to an acute inpatient rehabilitation unit. In addition, there was no significant difference in 30-day readmission rates between primary and revision TKA (P = .081). One primary TKA patient (0.4%) and 2 revision TKA patients (4%) were readmitted within 30 days after surgery (P = .081). The primary TKA readmission was for severe spasticity and a history of cerebral palsy leading to a quadriceps avulsion fracture from the superior pole of the patella. One revision TKA readmission was for acute periprosthetic joint infection, and the other for periprosthetic fracture around a press-fit distal femoral replacement stem. There was no significant difference in number of 30-day reoperations between the groups (P = .993). None of the primary TKAs and 2 (4%) of the revision TKAs underwent reoperation. Of the revision TKA patients who returned to the operating room within 30 days after surgery, one was treated for an acute periprosthetic joint infection, the other for a femoral periprosthetic fracture.

Discussion

Advances in multidisciplinary co-management of TKA patients and their clinical effects are highlighted in the TJR-PSH.¹⁴ TJR-PSH allows the health team and the patient to prepare for surgery with an understanding of probable outcomes and to optimize the patient’s medical and educational standing to better meet expectations and increase satisfaction.

Previous studies have focused on the etiologies of revision TKA^7,8 and on understanding the factors that may predict increased risk for a poor outcome after primary TKA and indicate a possible need for revision.^8,12 The present study focused on practical clinical processes that could potentially constitute a standardized perioperative protocol for revision TKA. An organized TJR-PSH may allow the health team to educate patients that LOS, rehabilitation and acute recovery, risk of acute (30-day) complications, and risk of readmission and return to the operating room within the first 30 days after surgery are similar for revision and primary TKAs, as long as proper preoperative optimization and education occur within the TJR-PSH.

Studies have found correlations between revision TKA and significantly increased LOS and postoperative complications.^20,21 In contrast, we found no significant difference in LOS between our primary and revision TKA groups. LOS was 2.6 days for primary TKA and 2.9 days for revision TKA—a significant improvement in care and cost for revision TKA patients. That the reduced mean LOS for revision TKA is similar to the mean LOS for primary TKA also implies a reduction in the higher cost of care in revision TKA.²⁰ In addition to obtaining similar LOS for primary and revision TKA, TJR-PSH achieved an overall reduction in LOS.^17,22Our results also showed no difference in discharge disposition between primary and revision TKA in our protocol. Discharge disposition also did not correlate with age, sex, BMI, ASA score, or CCI. In TJR-PSH, discharge planning starts before admission and is patient-oriented for optimal recovery. About 66% of primary TKA patients and 58% of revision TKA patients in our cohort were discharged home—implying we are able to send a majority of our postoperative patients home after a shorter hospital stay, while obtaining the same good outcomes. Discharging fewer revision TKA patients to extended-care facilities also indicates a possible reduction in the cost of postoperative care, bringing it in line with the cost in primary TKA. Early individualized discharge planning in TJA-PSH accounts for the similar outcomes in primary and revision TKAs.

There was no significant difference in 30-day readmission rates between our primary and revision TKA patients. An important component of the TJR-PSH pathway is the individualized postdischarge recovery plan, which helps with optimal recovery and reduces readmission rates. Our cohort’s 30-day readmission rate was 0.4% for primary TKA and 4% for revision TKA (P = .081). Thirty-day readmission is a good indicator of postoperative complications and recovery from surgery. We have previously reported on primary TKA outcomes.^{14,15,,18,22,23} In a study using an NSQIP (National Surgical Quality Improvement Program) database, 11,814 primary TKAs had a 30-day readmission rate of 4.2%.¹⁸ In an outcomes study of 17,994 patients who underwent primary TKA in a single fiscal year, the 30-day readmission rate was 5.9%.⁹ In addition, in a single-institution cohort study of 1032 primary TKA patients, Schairer and colleagues²³ found a 30-day unplanned readmission rate of 3.4%. Compared with primary TKA, revision TKA traditionally has had a higher postoperative complication rate.^20,21 There is also concern that shorter hospital stays may indicate that significant complications of revision TKAs are being missed. In this study, however, we established that the equal outcomes obtained in the perioperative period carry over to the 30-day postoperative period in our revision TKA group. Good postoperative follow-up and planning are important factors in readmission reduction. Readmissions also have significant overall cost implications.²⁴There was no statistical difference in 30-day reoperation rates between our primary and revision TKA patients. The primary TKA patients had no 30-day reoperations. Previous studies have found reoperation rates ranging from 1.8% to 4.7%.^25,26 Revision TKA patients are up to 6 times more likely than primary TKA patients to require reoperation.²⁰ Our study found no significant difference in outcomes between primary and revision TKAs.

Comparison of the outcomes of primary TKA and revision TKA in TJR-PSH showed no difference in acute recovery from surgery. LOS and discharge disposition, 30-day readmission rate, and 30-day return to the operating room were the same for primary and revision TKAs. The morbidity gap between primary and revision TKA patients has been closed in our research cohort. This outcome is important, as indications for primary TKA continue to expand and more primary TKAs are performed in younger patients.^18,23 The implication is that, in the future, more knees will need to be revised as patients outlive their prostheses.

Our study had some limitations. First, it involved a small sample of patients, operated on by a single surgeon in a well-organized TJR-PSH at a large academic center. This population might not represent the US patient population, but that should not have adversely affected data analysis, because patients were compared with a similar population. Second, the data might be incomplete because some patients with complications might have sought care at other medical facilities, and we might not have been aware of these cases. Third, we focused on objective clinical outcomes in order to measure the success of TKAs. We did not include any subjective, patient-reported data, such as rehabilitation advances and functioning levels. Fourth, multiple parameters can be used to address complication outcomes, but we used LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate because current payers and institutions often consider these variables when assessing quality of care. These parameters can be influenced by factors such as inpatient physical therapy goals, facility discharge practices, individual social support structure, and hospital pay-for-performance model. The implication is that different facilities have different outcomes in terms of LOS, discharge disposition, readmissions, and reoperations. However, we expect proportionate similarities in these parameters as patient perioperative outcomes become more complicated. Nevertheless, a multicenter study would be able to answer questions raised by this limitation. Fifth, our statistical analysis might have been affected by decreased power of some of the outcome variables.

TJR-PSH has succeeded in closing the perioperative morbidity and outcomes gap between primary and revision TKAs. Outcome parameters used to measure the success of TJR-PSH are standard measures of the immediate postoperative recovery and short-term outcomes of TKA patients. These measures are linked to complication rates and overall outcomes in many TKA studies.^14,15,17,19 Also important is that hospital costs can be drastically cut by reducing LOS, readmissions, and reoperations. Presence of any complication of primary or revision TKA raises the cost up to 34%. This increase can go as high as 64% in the 90 days after surgery.²⁷

Conclusion

The major challenge of the changing medical landscape is to integrate quality care and a continually improving healthcare system with the goal of cost-effective delivery of healthcare. Surgical care costs can be significantly increased by evitable hospital stays, complications that lead to readmissions, and unplanned returns to the operating room after index surgery. The new perioperative surgical home created for TJA has helped drastically reduce LOS, discharge disposition, 30-day readmission rate, and 30-day reoperation rate in revision TKA. This study demonstrates similar outcomes in our revision TKA patients relative to their primary TKA counterparts.

Am J Orthop. 2016;45(7):E458-E464. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

Internet-delivered cognitive-behavioral therapy is effective at overcoming chronic insomnia, a randomized controlled trial of 303 adults showed.

In the trial, patients who were randomized to receive cognitive-behavioral therapy for insomnia (CBT-I) used a Web-based program called Sleep Healthy Using the Internet (SHUTi), which “incorporates the primary tenets of face-to-face CBT-I, including sleep restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse prevention,” wrote Lee M. Ritterband, PhD, and his associates. Meanwhile, patients in the control group received online, nonspecific patient education.

©Karen Winton/iStockphoto

[email protected]

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

See related editorial

More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.^1–3 In various studies,^4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.

THREE CATEGORIES OF RISK

Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).^7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.⁹ Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).¹⁰

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes⁸:

• Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
• An absolute decrease in systolic blood pressure of 40 mm Hg or more
• Need for inotropic support
• Cardiac arrest
• Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.^11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).¹⁰

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.¹⁰

DIAGNOSING SUBMASSIVE PULMONARY EMBOLISM, DELINEATING ITS SEVERITY

In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.¹²

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

• Evidence of new complete or incomplete right bundle branch block
• T-wave inversion in the anterolateral leads V₁ to V₄
• S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).¹³ 

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.¹⁴

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.¹⁵ Abnormal levels of these substances are as follows:

• Troponin T greater than 0.1 ng/mL
• Troponin I greater than 0.4 ng/mL
• BNP greater than 90 pg/mL
• NT-pro-BNP greater than 500 pg/mL
• H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,^14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.¹⁸ Evidence of right ventricular dysfunction includes the following:

• New-onset hypokinesis or akinesis
• Right ventricular dilation
• Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
• Paradoxical movement of the interventricular septum
• Newly increased right ventricular systolic pressure
• Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.^15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following^20,21:

• A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
• Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.²²

THROMBOLYTIC AGENTS

Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.

Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.²³

To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.²⁴

Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.

Complications of thrombolytic therapy

Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.

A meta-analysis²⁵ of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:

• 210 (9.88%) in the low-risk category
• 1,499 (70.54%) in the submassive category
• 31 (1.46%) in the massive category
• 385 (18.11%) whose disease severity could not be determined.

Major bleeding occurred in:

• 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
• 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).

Intracranial hemorrhage occurred in:

• 15 (1.46%) of 2,014 patients on thrombolytic therapy
• 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).

Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).

Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.

These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.

Table 3 lists absolute and relative contraindications to thrombolytic therapy.

MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM

The MAPPET-3 trial

The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,²⁶ in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.

In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.

Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.

Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.

Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).

Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.²⁷

MOPETT trial

The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial²⁸ was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.

The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.

The primary outcome was the development of pulmonary hypertension, based on echocardiography.

Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.

Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.

PEITHO trial

The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial²⁹ was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.

The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.

Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.

Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.

Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.¹

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.²

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.³

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.⁴ Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.⁵

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.⁶ A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.⁷

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.⁸

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.⁹

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).¹⁰

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.¹¹

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.¹²

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).¹³

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.⁷

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.¹⁴

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.¹⁵ In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.¹⁶

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.¹⁷

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.¹⁸ Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,¹⁹ and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.²⁰ Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.²¹

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.²²

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.²³ Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al²⁴ revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.²⁵

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.²⁷ Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.²⁸

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.²⁹

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,²³ the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.²³

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.³⁰

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.³¹

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.³²

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.³³

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.³⁴

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.³⁵

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.³⁵ Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.^35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.³⁸

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.³⁹ Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.⁴⁰

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.⁴¹ Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.⁴²

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.⁴⁰ Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.⁴³

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.⁴⁴

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.⁴⁵ However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.⁴⁶ This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.⁴⁷

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.⁴⁸ In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.⁴⁹

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.⁵⁰

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation⁵¹:

• Total radiation dose to the heart > 40 Gy
• Delay of 10 years or more since therapy
• Abnormal interval electrocardiographic changes such as bundle branch block
• Prior pericardial involvement
• Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).¹⁰ The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.¹⁰

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.⁵² The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).⁵³

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.⁵⁴ These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.⁵⁵

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.^56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.^58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.