Week in, week out for the past 25 years, I have had a front-row seat to the medical practice of a certain female physician: my wife, Heather. We met when we worked together on the wards during residency in 1991; spent a year in rural Montana working together in clinics, ERs, and hospitals; shared the care of one another’s patients as our practices grew in parallel – hers in skilled nursing facilities, mine in the hospital; and reunited in recent years to work together as part of the same practice.

She spends more time considering her approach to a challenging case.

She has less urgency in deciding on a definitive course of action and more patience in sorting things out before proceeding with a diagnostic and therapeutic plan. She is more likely to leave open the possibility of changing her mind; she has less of a tendency to anchor on a particular diagnosis and treatment. Put another way, she is more willing to continue with ambiguous findings without lateralizing to one particular approach.

She brings more work-life balance to her professional responsibilities.

Despite being highly productive at work (and at home), she has worked less than full time throughout her career. This means that, during any given patient encounter, she is more likely to be unburdened by overwork and its negative consequences. It is my sense that many full-time physicians would be happier (and more effective) if they simply worked less. Heather has had the self-knowledge to take on a more manageable workload; the result is that she has remained joyous in practice for more than two decades.

She is less dogmatic and more willing to customize care based on the needs of the individual patient.

Although a good fund of knowledge is essential, if such knowledge obscures the physician’s ability to read the patient, then it is best abandoned, at least temporarily. Heather refers to the body of scientific evidence frequently, but she reserves an equal or greater portion of her cognitive bandwidth for the patient she is caring for at a particular moment.

How might the observations of this case study help to derive meaning from the study by Dr. Tsugawa and his associates, so that all patients may benefit from whatever it is that female physicians do to achieve better outcomes?

First, if physicians – regardless of gender – simply have an awareness of anchoring bias or rushing to land on a diagnosis or treatment, they will be less likely to do so in the future.

Next, we can learn that avoiding overwork can make for more joy in work, and if this is so, our patients may fare better. When I say “avoiding overwork,” that might mean rethinking our assumptions underlying the amount of work we take on.

Finally, while amassing a large fund of knowledge is a good thing, balancing medical knowledge with knowledge of the individual patient is crucial to good medical practice.
 

Dr. Whitcomb is Chief Medical Officer at Remedy Partners in Darien, CT. He is a cofounder and past president of SHM. Email him at [email protected].

Week in, week out for the past 25 years, I have had a front-row seat to the medical practice of a certain female physician: my wife, Heather. We met when we worked together on the wards during residency in 1991; spent a year in rural Montana working together in clinics, ERs, and hospitals; shared the care of one another’s patients as our practices grew in parallel – hers in skilled nursing facilities, mine in the hospital; and reunited in recent years to work together as part of the same practice.

She spends more time considering her approach to a challenging case.

She has less urgency in deciding on a definitive course of action and more patience in sorting things out before proceeding with a diagnostic and therapeutic plan. She is more likely to leave open the possibility of changing her mind; she has less of a tendency to anchor on a particular diagnosis and treatment. Put another way, she is more willing to continue with ambiguous findings without lateralizing to one particular approach.

She brings more work-life balance to her professional responsibilities.

Despite being highly productive at work (and at home), she has worked less than full time throughout her career. This means that, during any given patient encounter, she is more likely to be unburdened by overwork and its negative consequences. It is my sense that many full-time physicians would be happier (and more effective) if they simply worked less. Heather has had the self-knowledge to take on a more manageable workload; the result is that she has remained joyous in practice for more than two decades.

She is less dogmatic and more willing to customize care based on the needs of the individual patient.

Although a good fund of knowledge is essential, if such knowledge obscures the physician’s ability to read the patient, then it is best abandoned, at least temporarily. Heather refers to the body of scientific evidence frequently, but she reserves an equal or greater portion of her cognitive bandwidth for the patient she is caring for at a particular moment.

How might the observations of this case study help to derive meaning from the study by Dr. Tsugawa and his associates, so that all patients may benefit from whatever it is that female physicians do to achieve better outcomes?

First, if physicians – regardless of gender – simply have an awareness of anchoring bias or rushing to land on a diagnosis or treatment, they will be less likely to do so in the future.

Next, we can learn that avoiding overwork can make for more joy in work, and if this is so, our patients may fare better. When I say “avoiding overwork,” that might mean rethinking our assumptions underlying the amount of work we take on.

Finally, while amassing a large fund of knowledge is a good thing, balancing medical knowledge with knowledge of the individual patient is crucial to good medical practice.
 

Dr. Whitcomb is Chief Medical Officer at Remedy Partners in Darien, CT. He is a cofounder and past president of SHM. Email him at [email protected].

Week in, week out for the past 25 years, I have had a front-row seat to the medical practice of a certain female physician: my wife, Heather. We met when we worked together on the wards during residency in 1991; spent a year in rural Montana working together in clinics, ERs, and hospitals; shared the care of one another’s patients as our practices grew in parallel – hers in skilled nursing facilities, mine in the hospital; and reunited in recent years to work together as part of the same practice.

She spends more time considering her approach to a challenging case.

She has less urgency in deciding on a definitive course of action and more patience in sorting things out before proceeding with a diagnostic and therapeutic plan. She is more likely to leave open the possibility of changing her mind; she has less of a tendency to anchor on a particular diagnosis and treatment. Put another way, she is more willing to continue with ambiguous findings without lateralizing to one particular approach.

She brings more work-life balance to her professional responsibilities.

Despite being highly productive at work (and at home), she has worked less than full time throughout her career. This means that, during any given patient encounter, she is more likely to be unburdened by overwork and its negative consequences. It is my sense that many full-time physicians would be happier (and more effective) if they simply worked less. Heather has had the self-knowledge to take on a more manageable workload; the result is that she has remained joyous in practice for more than two decades.

She is less dogmatic and more willing to customize care based on the needs of the individual patient.

Although a good fund of knowledge is essential, if such knowledge obscures the physician’s ability to read the patient, then it is best abandoned, at least temporarily. Heather refers to the body of scientific evidence frequently, but she reserves an equal or greater portion of her cognitive bandwidth for the patient she is caring for at a particular moment.

How might the observations of this case study help to derive meaning from the study by Dr. Tsugawa and his associates, so that all patients may benefit from whatever it is that female physicians do to achieve better outcomes?

First, if physicians – regardless of gender – simply have an awareness of anchoring bias or rushing to land on a diagnosis or treatment, they will be less likely to do so in the future.

Next, we can learn that avoiding overwork can make for more joy in work, and if this is so, our patients may fare better. When I say “avoiding overwork,” that might mean rethinking our assumptions underlying the amount of work we take on.

Finally, while amassing a large fund of knowledge is a good thing, balancing medical knowledge with knowledge of the individual patient is crucial to good medical practice.
 

Dr. Whitcomb is Chief Medical Officer at Remedy Partners in Darien, CT. He is a cofounder and past president of SHM. Email him at [email protected].

HOLLYWOOD, FLA – The radiopaque contrast agent Gastrografin accurately diagnosed the majority of small bowel obstructions, allowing surgeons to identify which patients needed emergent surgery and which could be managed conservatively.

When instilled via nasogastric tube, the diatrizoate solution had a 92% positive predictive value for adhesive small bowel obstruction, Martin D. Zielinski, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

[email protected]

On Twitter @alz_gal

HOLLYWOOD, FLA – The radiopaque contrast agent Gastrografin accurately diagnosed the majority of small bowel obstructions, allowing surgeons to identify which patients needed emergent surgery and which could be managed conservatively.

When instilled via nasogastric tube, the diatrizoate solution had a 92% positive predictive value for adhesive small bowel obstruction, Martin D. Zielinski, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

[email protected]

On Twitter @alz_gal

HOLLYWOOD, FLA – The radiopaque contrast agent Gastrografin accurately diagnosed the majority of small bowel obstructions, allowing surgeons to identify which patients needed emergent surgery and which could be managed conservatively.

When instilled via nasogastric tube, the diatrizoate solution had a 92% positive predictive value for adhesive small bowel obstruction, Martin D. Zielinski, MD, said at the annual scientific assembly of the Eastern Association for the Surgery of Trauma.

[email protected]

On Twitter @alz_gal

Childhood pneumococcal conjugate vaccines continue to indirectly produce widespread societal protection against invasive pneumococcal disease, a review and meta-analysis showed.

In fact, the reviewed studies suggest that the use of these vaccines in children can lead to an overall 90% drop in invasive pneumococcal disease within fewer than 10 years.

Herd immunity appears to be at work, the review authors said. The effect is so powerful that the findings raise questions about “the merit of offering [the 13-valent pneumococcal vaccine] in older groups” in places that have a children’s pneumococcal conjugate vaccine (PCV) program, the investigators said.

U.S. guidelines recommend vaccinations for older people, although the recommendations are up for review in 2018.

According to the review, childhood PCVs have had a tremendous impact since a seven-valent version (PCV7) was first released in 2000. “In vaccinated young children, disease due to serotypes included in the vaccines has been reduced to negligible levels,” the authors wrote.

But unvaccinated people, especially the elderly, remain susceptible.

The review authors, led by Tinevimbo Shiri, PhD, of the University of Warwick, Coventry, England, updated a 2013 systemic review (Vaccine. 2013 Dec 17;32[1]:133-45). They focused on studies from 1994 to 2016 that examined the effects of introducing PCV in children.

A total of 242 studies were included in the meta-analysis, published in the January issue of Lancet Global Health (2017 Jan;5[1]:e51-e9), including 70 from the previous review. Of these, only 9 (4%) were performed in poor or middle-income countries, with most of the rest having been done in North America (42%) and Europe (38%).

The researchers found that “[herd] immunity effects continued to accumulate over time and reduced disease due to PCV7 serotypes, for which follow-up data have generally been available for the longest period, with a 90% average reduction after about 9 years.”

Specifically, the review estimated it would take 8.9 years for a 90% reduction in invasive pneumococcal disease for grouped serotypes in the PCV7 and 9.5 years for the extra six grouped serotypes in the 13-valent PCV. The latter vaccine was introduced in 2010.

The researchers found evidence of a similar annual reduction in disease linked to grouped serotypes in the 23-valent pneumococcal polysaccharide vaccine in adults aged 19 and up. They noted that the 11 serotypes contained in PPV23 but not in PCV13 “did not change invasive pneumococcal disease at any age.”

The investigators added: “In countries with mature pediatric PCV programmes such as Canada, Germany, the Netherlands, the U.K., and the U.S.A., invasive pneumococcal disease due to PCV7 serotypes has been nearly eliminated through indirect protection - i.e., the average incidence of PCV7-invasive pneumococcal disease after nearly a decade of PCV7 use is less than 10 per 100,000 people. In these countries, consistent decreases in vaccine-type adult community-acquired pneumonia (CAP) or meningitis, and nonbacteraemic CAP, have been observed, indicating substantial indirect protection effects against noninvasive disease from childhood vaccination.”

The review authors noted that a major “evidence gap” in the effectiveness of childhood PCV programs in low-income countries exists. “Because these countries are increasingly undertaking childhood vaccination programs, research to assess the indirect effects in these settings is particularly relevant,” they wrote.

The review’s limitations include the possibility that the results could be thrown off by variations across nations in areas like diagnostic protocols, surveillance, and outcome measures.

The authors of the review, funded by the Policy Research Program of England’s Department of Health, reported no relevant financial disclosures.

Childhood pneumococcal conjugate vaccines continue to indirectly produce widespread societal protection against invasive pneumococcal disease, a review and meta-analysis showed.

In fact, the reviewed studies suggest that the use of these vaccines in children can lead to an overall 90% drop in invasive pneumococcal disease within fewer than 10 years.

Herd immunity appears to be at work, the review authors said. The effect is so powerful that the findings raise questions about “the merit of offering [the 13-valent pneumococcal vaccine] in older groups” in places that have a children’s pneumococcal conjugate vaccine (PCV) program, the investigators said.

U.S. guidelines recommend vaccinations for older people, although the recommendations are up for review in 2018.

According to the review, childhood PCVs have had a tremendous impact since a seven-valent version (PCV7) was first released in 2000. “In vaccinated young children, disease due to serotypes included in the vaccines has been reduced to negligible levels,” the authors wrote.

But unvaccinated people, especially the elderly, remain susceptible.

The review authors, led by Tinevimbo Shiri, PhD, of the University of Warwick, Coventry, England, updated a 2013 systemic review (Vaccine. 2013 Dec 17;32[1]:133-45). They focused on studies from 1994 to 2016 that examined the effects of introducing PCV in children.

A total of 242 studies were included in the meta-analysis, published in the January issue of Lancet Global Health (2017 Jan;5[1]:e51-e9), including 70 from the previous review. Of these, only 9 (4%) were performed in poor or middle-income countries, with most of the rest having been done in North America (42%) and Europe (38%).

The researchers found that “[herd] immunity effects continued to accumulate over time and reduced disease due to PCV7 serotypes, for which follow-up data have generally been available for the longest period, with a 90% average reduction after about 9 years.”

Specifically, the review estimated it would take 8.9 years for a 90% reduction in invasive pneumococcal disease for grouped serotypes in the PCV7 and 9.5 years for the extra six grouped serotypes in the 13-valent PCV. The latter vaccine was introduced in 2010.

The researchers found evidence of a similar annual reduction in disease linked to grouped serotypes in the 23-valent pneumococcal polysaccharide vaccine in adults aged 19 and up. They noted that the 11 serotypes contained in PPV23 but not in PCV13 “did not change invasive pneumococcal disease at any age.”

The investigators added: “In countries with mature pediatric PCV programmes such as Canada, Germany, the Netherlands, the U.K., and the U.S.A., invasive pneumococcal disease due to PCV7 serotypes has been nearly eliminated through indirect protection - i.e., the average incidence of PCV7-invasive pneumococcal disease after nearly a decade of PCV7 use is less than 10 per 100,000 people. In these countries, consistent decreases in vaccine-type adult community-acquired pneumonia (CAP) or meningitis, and nonbacteraemic CAP, have been observed, indicating substantial indirect protection effects against noninvasive disease from childhood vaccination.”

The review authors noted that a major “evidence gap” in the effectiveness of childhood PCV programs in low-income countries exists. “Because these countries are increasingly undertaking childhood vaccination programs, research to assess the indirect effects in these settings is particularly relevant,” they wrote.

The review’s limitations include the possibility that the results could be thrown off by variations across nations in areas like diagnostic protocols, surveillance, and outcome measures.

The authors of the review, funded by the Policy Research Program of England’s Department of Health, reported no relevant financial disclosures.

Childhood pneumococcal conjugate vaccines continue to indirectly produce widespread societal protection against invasive pneumococcal disease, a review and meta-analysis showed.

In fact, the reviewed studies suggest that the use of these vaccines in children can lead to an overall 90% drop in invasive pneumococcal disease within fewer than 10 years.

Herd immunity appears to be at work, the review authors said. The effect is so powerful that the findings raise questions about “the merit of offering [the 13-valent pneumococcal vaccine] in older groups” in places that have a children’s pneumococcal conjugate vaccine (PCV) program, the investigators said.

U.S. guidelines recommend vaccinations for older people, although the recommendations are up for review in 2018.

According to the review, childhood PCVs have had a tremendous impact since a seven-valent version (PCV7) was first released in 2000. “In vaccinated young children, disease due to serotypes included in the vaccines has been reduced to negligible levels,” the authors wrote.

But unvaccinated people, especially the elderly, remain susceptible.

The review authors, led by Tinevimbo Shiri, PhD, of the University of Warwick, Coventry, England, updated a 2013 systemic review (Vaccine. 2013 Dec 17;32[1]:133-45). They focused on studies from 1994 to 2016 that examined the effects of introducing PCV in children.

A total of 242 studies were included in the meta-analysis, published in the January issue of Lancet Global Health (2017 Jan;5[1]:e51-e9), including 70 from the previous review. Of these, only 9 (4%) were performed in poor or middle-income countries, with most of the rest having been done in North America (42%) and Europe (38%).

The researchers found that “[herd] immunity effects continued to accumulate over time and reduced disease due to PCV7 serotypes, for which follow-up data have generally been available for the longest period, with a 90% average reduction after about 9 years.”

Specifically, the review estimated it would take 8.9 years for a 90% reduction in invasive pneumococcal disease for grouped serotypes in the PCV7 and 9.5 years for the extra six grouped serotypes in the 13-valent PCV. The latter vaccine was introduced in 2010.

The researchers found evidence of a similar annual reduction in disease linked to grouped serotypes in the 23-valent pneumococcal polysaccharide vaccine in adults aged 19 and up. They noted that the 11 serotypes contained in PPV23 but not in PCV13 “did not change invasive pneumococcal disease at any age.”

The investigators added: “In countries with mature pediatric PCV programmes such as Canada, Germany, the Netherlands, the U.K., and the U.S.A., invasive pneumococcal disease due to PCV7 serotypes has been nearly eliminated through indirect protection - i.e., the average incidence of PCV7-invasive pneumococcal disease after nearly a decade of PCV7 use is less than 10 per 100,000 people. In these countries, consistent decreases in vaccine-type adult community-acquired pneumonia (CAP) or meningitis, and nonbacteraemic CAP, have been observed, indicating substantial indirect protection effects against noninvasive disease from childhood vaccination.”

The review authors noted that a major “evidence gap” in the effectiveness of childhood PCV programs in low-income countries exists. “Because these countries are increasingly undertaking childhood vaccination programs, research to assess the indirect effects in these settings is particularly relevant,” they wrote.

The review’s limitations include the possibility that the results could be thrown off by variations across nations in areas like diagnostic protocols, surveillance, and outcome measures.

The authors of the review, funded by the Policy Research Program of England’s Department of Health, reported no relevant financial disclosures.

Individuals at risk of losing health insurance with a potential repeal of the Affordable Care Act have significantly higher rates of self-reported poor health and are more likely to have certain chronic diseases, according to a research letter published Jan. 20 in JAMA Internal Medicine.

Researchers looked at data from the National Health Interview Survey, focusing on the three groups of adults under 65 years who would be most likely to lose their health insurance if the ACA were repealed: those with incomes below 400% of the federal poverty level (FPL) who purchased insurance through the health insurance exchanges, childless adults with incomes below 138% of the FPL who gained coverage via expanded Medicaid, and Medicaid-enrolled parents or adults in families with children who did not receive disability insurance and whose income was 50%-138% of the FPL.

“Approximately 20 million individuals have gained health insurance under the Affordable Care Act (ACA), including young adults covered under parental insurance, those purchasing private insurance on exchanges, and those covered through state Medicaid expansion,” wrote Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health, Minneapolis, and her coauthors. “As of mid-2016, 10.4 million individuals had private insurance policies through the exchanges, of whom 84% had incomes below 400% of the federal poverty level (FPL) and received premium tax credits.”

Compared with adults under 65 who had employer-sponsored health insurance, adults in these three groups were significantly more likely to self-report their health as “fair or poor” (JAMA Intern Med. 2017 Jan 20. doi: 10.1001/jamainternmed.2016.9541).

Adults without children and with incomes below 138% of the federal poverty level also had a significantly greater incidence of hypertension, coronary heart disease, cancer, diabetes, stroke, or any heart condition, compared with individuals with employer-sponsored insurance.

They were also significantly more likely to have visited a physician 10 or more times or visited the emergency department at least twice in the past year, and to have undergone surgery in the past year.

“Our analysis highlights the socioeconomic vulnerability and rates of chronic diseases and health care utilization of individuals at risk to lose health insurance if the ACA is modified or repealed,” according to Dr. Karaca-Mandic. “These consequences point to the challenges Congress should address before enacting new health care legislation.”

The study was supported by the NIH Early Independence Award. One author declared consulting fees from the pharmaceutical industry, and another declared private sector support through Yale University. No other conflicts of interest were declared.

Individuals at risk of losing health insurance with a potential repeal of the Affordable Care Act have significantly higher rates of self-reported poor health and are more likely to have certain chronic diseases, according to a research letter published Jan. 20 in JAMA Internal Medicine.

Researchers looked at data from the National Health Interview Survey, focusing on the three groups of adults under 65 years who would be most likely to lose their health insurance if the ACA were repealed: those with incomes below 400% of the federal poverty level (FPL) who purchased insurance through the health insurance exchanges, childless adults with incomes below 138% of the FPL who gained coverage via expanded Medicaid, and Medicaid-enrolled parents or adults in families with children who did not receive disability insurance and whose income was 50%-138% of the FPL.

“Approximately 20 million individuals have gained health insurance under the Affordable Care Act (ACA), including young adults covered under parental insurance, those purchasing private insurance on exchanges, and those covered through state Medicaid expansion,” wrote Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health, Minneapolis, and her coauthors. “As of mid-2016, 10.4 million individuals had private insurance policies through the exchanges, of whom 84% had incomes below 400% of the federal poverty level (FPL) and received premium tax credits.”

Compared with adults under 65 who had employer-sponsored health insurance, adults in these three groups were significantly more likely to self-report their health as “fair or poor” (JAMA Intern Med. 2017 Jan 20. doi: 10.1001/jamainternmed.2016.9541).

Adults without children and with incomes below 138% of the federal poverty level also had a significantly greater incidence of hypertension, coronary heart disease, cancer, diabetes, stroke, or any heart condition, compared with individuals with employer-sponsored insurance.

They were also significantly more likely to have visited a physician 10 or more times or visited the emergency department at least twice in the past year, and to have undergone surgery in the past year.

“Our analysis highlights the socioeconomic vulnerability and rates of chronic diseases and health care utilization of individuals at risk to lose health insurance if the ACA is modified or repealed,” according to Dr. Karaca-Mandic. “These consequences point to the challenges Congress should address before enacting new health care legislation.”

The study was supported by the NIH Early Independence Award. One author declared consulting fees from the pharmaceutical industry, and another declared private sector support through Yale University. No other conflicts of interest were declared.

Individuals at risk of losing health insurance with a potential repeal of the Affordable Care Act have significantly higher rates of self-reported poor health and are more likely to have certain chronic diseases, according to a research letter published Jan. 20 in JAMA Internal Medicine.

Researchers looked at data from the National Health Interview Survey, focusing on the three groups of adults under 65 years who would be most likely to lose their health insurance if the ACA were repealed: those with incomes below 400% of the federal poverty level (FPL) who purchased insurance through the health insurance exchanges, childless adults with incomes below 138% of the FPL who gained coverage via expanded Medicaid, and Medicaid-enrolled parents or adults in families with children who did not receive disability insurance and whose income was 50%-138% of the FPL.

“Approximately 20 million individuals have gained health insurance under the Affordable Care Act (ACA), including young adults covered under parental insurance, those purchasing private insurance on exchanges, and those covered through state Medicaid expansion,” wrote Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health, Minneapolis, and her coauthors. “As of mid-2016, 10.4 million individuals had private insurance policies through the exchanges, of whom 84% had incomes below 400% of the federal poverty level (FPL) and received premium tax credits.”

Compared with adults under 65 who had employer-sponsored health insurance, adults in these three groups were significantly more likely to self-report their health as “fair or poor” (JAMA Intern Med. 2017 Jan 20. doi: 10.1001/jamainternmed.2016.9541).

Adults without children and with incomes below 138% of the federal poverty level also had a significantly greater incidence of hypertension, coronary heart disease, cancer, diabetes, stroke, or any heart condition, compared with individuals with employer-sponsored insurance.

They were also significantly more likely to have visited a physician 10 or more times or visited the emergency department at least twice in the past year, and to have undergone surgery in the past year.

“Our analysis highlights the socioeconomic vulnerability and rates of chronic diseases and health care utilization of individuals at risk to lose health insurance if the ACA is modified or repealed,” according to Dr. Karaca-Mandic. “These consequences point to the challenges Congress should address before enacting new health care legislation.”

The study was supported by the NIH Early Independence Award. One author declared consulting fees from the pharmaceutical industry, and another declared private sector support through Yale University. No other conflicts of interest were declared.

Scabies

BY JENNA BOROK AND LAWRENCE EICHENFIELD, MD

The scabies mite or the “itch mite” was discovered in 1687 as the first identifiable microorganism that caused human disease.1 Scabies is an infection of the epidermis with the mite, Sarcoptes scabiei variety hominis (S. scabiei) affecting approximately 300 million people worldwide.2 It is a common disease, especially among school-aged children and is particularly rampant in areas of poor sanitation and overcrowding.2,3

S. scabiei live in and on human skin where the impregnated female mite burrows into the stratum corneum and lays two to three eggs daily for as long as 30 days.3,4 The egg becomes a larva, which leaves the burrow and molts into a nymph, and it continues to molt into a mature mite.3 Mating then occurs during the mite stage. After mating, the male mite dies and the female completes the life cycle by burrowing back into the stratum corneum; this process takes about 2 weeks.3,4

Diagnosis

The diagnosis is usually based on strong clinical suspicion. The chief complaint is often a generalized itching rash that is often worse at nighttime.3,6 Small inflammatory papules are the main physical exam finding, and they usually are widely distributed, the favored locations including the finger webs, wrists, elbows, axillae, girdle area, and feet.3 In addition, male genitalia oftentimes are involved, and small itching papules on the penis should be considered scabies until proven otherwise.3 The head almost always is spared except in infants, who may present with pustules on the palms and soles of the feet and vesicles or lesions on the neck and face.7

The pathognomonic exam finding is the mite’s burrow, which appears as a 2-5 mm white, superficial, threadlike line. Upon close inspection, a tiny black speck often can be seen at the end of the burrow, which represents the adult mite.3 The presence of mites, eggs, or feces also is diagnostic and is accomplished by a skin scraping with a No. 15 blade.3 A positive scraping is diagnostic, although a negative scraping does not rule out the condition. (We explain this to our patients by saying “If you call someone’s home phone and they answer the phone, you know they are home. If you call and there is no answer, it could be that they aren’t home, or they are home and just not answering.”) A biopsy usually is not required, but may provide a diagnosis when scabies is unsuspected.3

The differential for red papules that itch in children includes atopic dermatitis, impetigo, papular urticaria, contact dermatitis, and other infestations, including bites from mosquitoes, fleas, and bed bugs. Atopic dermatitis (AD) can present as eczematous, erythematous papular lesions with oozing in flexural areas similar to areas affected by scabies. However, there are no burrows seen in AD, and the lesions are not in the interdigital web spaces. Impetigo has erythematous vesiculopustular lesions that form honey-colored crusts. Papular urticaria may be a hypersensitivity reaction to another insect, and the urticarial lesions are usually on the exposed parts of extremities. Unlike scabies, there are no burrows and usually no symptomatic family members. Contact dermatitis can present with vesicular, bullous, and sometimes papular erythematous lesions. It occurs after exposure to an allergen and often has well-demarcated borders with geometric shapes.

Treatment

Few randomized control or head-to-head trials exist on scabies treatment.2 First-line treatment is permethrin 5% cream, which is applied to the entire body surface from the neck down in children, but includes the face and scalp in infants.8,9 It is applied at bedtime and is washed off in the morning, and a second application is recommended after 7 days.3,8 It can be used in infants 2 months of age and older, and in pregnant females.3 Household contacts should be treated too, and those who are asymptomatic only require one application of permethrin.3 Permethrin is effective and more cost effective than ivermectin. Oral ivermectin has been used to treat scabies with a dose of 0.2 mg/kg and then repeated 2 weeks later, but the safety in children under 15 kg has not been determined.9 Lindane is an alternative option and is not recommended as first-line therapy because of its toxicity. It only should be used if the patient cannot tolerate or failed the previously mentioned therapies, with particular concern in children less than 50 kg.8,9 Infants and young children should be treated with permethrin and not with lindane.8 Clothes and bed linens can be decontaminated by machine-washing at a hot temperature.3,8 Topical corticosteroids and oral antihistamines can be helpful post-treatment to minimize pruritus and secondary eczematous changes.9

References

1. Int J Dermatol. 1998 Aug;37(8):625-30.

2. Interventions for treating scabies. The Cochrane database of systematic reviews. 2007. doi: 10.1002/14651858.CD000320.pub2.

3. Lookingbill and Marks’ Principles of Dermatology, 5th edition (Philadelphia: Elsevier, 2013).

4. BMJ. 2005 Sep 17;331(7517):619-22.

5. Br Med J. 1941 Sep 20;2(4211):405-6.

6. Lancet. 2006 May 27;367(9524):1767-74.

7. Am J Clin Dermatol. 2002;3(1):9-18.

8. MMWR June 5, 2015 / 64(RR3);1-137.

9. Scabies in Red Book: 2015 Report of the Committee on Infectious Diseases (Am Acad Pediatrics. 2015; pp. 702-4).

Scabies

BY JENNA BOROK AND LAWRENCE EICHENFIELD, MD

The scabies mite or the “itch mite” was discovered in 1687 as the first identifiable microorganism that caused human disease.1 Scabies is an infection of the epidermis with the mite, Sarcoptes scabiei variety hominis (S. scabiei) affecting approximately 300 million people worldwide.2 It is a common disease, especially among school-aged children and is particularly rampant in areas of poor sanitation and overcrowding.2,3

S. scabiei live in and on human skin where the impregnated female mite burrows into the stratum corneum and lays two to three eggs daily for as long as 30 days.3,4 The egg becomes a larva, which leaves the burrow and molts into a nymph, and it continues to molt into a mature mite.3 Mating then occurs during the mite stage. After mating, the male mite dies and the female completes the life cycle by burrowing back into the stratum corneum; this process takes about 2 weeks.3,4

Diagnosis

The diagnosis is usually based on strong clinical suspicion. The chief complaint is often a generalized itching rash that is often worse at nighttime.3,6 Small inflammatory papules are the main physical exam finding, and they usually are widely distributed, the favored locations including the finger webs, wrists, elbows, axillae, girdle area, and feet.3 In addition, male genitalia oftentimes are involved, and small itching papules on the penis should be considered scabies until proven otherwise.3 The head almost always is spared except in infants, who may present with pustules on the palms and soles of the feet and vesicles or lesions on the neck and face.7

The pathognomonic exam finding is the mite’s burrow, which appears as a 2-5 mm white, superficial, threadlike line. Upon close inspection, a tiny black speck often can be seen at the end of the burrow, which represents the adult mite.3 The presence of mites, eggs, or feces also is diagnostic and is accomplished by a skin scraping with a No. 15 blade.3 A positive scraping is diagnostic, although a negative scraping does not rule out the condition. (We explain this to our patients by saying “If you call someone’s home phone and they answer the phone, you know they are home. If you call and there is no answer, it could be that they aren’t home, or they are home and just not answering.”) A biopsy usually is not required, but may provide a diagnosis when scabies is unsuspected.3

The differential for red papules that itch in children includes atopic dermatitis, impetigo, papular urticaria, contact dermatitis, and other infestations, including bites from mosquitoes, fleas, and bed bugs. Atopic dermatitis (AD) can present as eczematous, erythematous papular lesions with oozing in flexural areas similar to areas affected by scabies. However, there are no burrows seen in AD, and the lesions are not in the interdigital web spaces. Impetigo has erythematous vesiculopustular lesions that form honey-colored crusts. Papular urticaria may be a hypersensitivity reaction to another insect, and the urticarial lesions are usually on the exposed parts of extremities. Unlike scabies, there are no burrows and usually no symptomatic family members. Contact dermatitis can present with vesicular, bullous, and sometimes papular erythematous lesions. It occurs after exposure to an allergen and often has well-demarcated borders with geometric shapes.

Treatment

Few randomized control or head-to-head trials exist on scabies treatment.2 First-line treatment is permethrin 5% cream, which is applied to the entire body surface from the neck down in children, but includes the face and scalp in infants.8,9 It is applied at bedtime and is washed off in the morning, and a second application is recommended after 7 days.3,8 It can be used in infants 2 months of age and older, and in pregnant females.3 Household contacts should be treated too, and those who are asymptomatic only require one application of permethrin.3 Permethrin is effective and more cost effective than ivermectin. Oral ivermectin has been used to treat scabies with a dose of 0.2 mg/kg and then repeated 2 weeks later, but the safety in children under 15 kg has not been determined.9 Lindane is an alternative option and is not recommended as first-line therapy because of its toxicity. It only should be used if the patient cannot tolerate or failed the previously mentioned therapies, with particular concern in children less than 50 kg.8,9 Infants and young children should be treated with permethrin and not with lindane.8 Clothes and bed linens can be decontaminated by machine-washing at a hot temperature.3,8 Topical corticosteroids and oral antihistamines can be helpful post-treatment to minimize pruritus and secondary eczematous changes.9

References

1. Int J Dermatol. 1998 Aug;37(8):625-30.

2. Interventions for treating scabies. The Cochrane database of systematic reviews. 2007. doi: 10.1002/14651858.CD000320.pub2.

3. Lookingbill and Marks’ Principles of Dermatology, 5th edition (Philadelphia: Elsevier, 2013).

4. BMJ. 2005 Sep 17;331(7517):619-22.

5. Br Med J. 1941 Sep 20;2(4211):405-6.

6. Lancet. 2006 May 27;367(9524):1767-74.

7. Am J Clin Dermatol. 2002;3(1):9-18.

8. MMWR June 5, 2015 / 64(RR3);1-137.

9. Scabies in Red Book: 2015 Report of the Committee on Infectious Diseases (Am Acad Pediatrics. 2015; pp. 702-4).

Scabies

BY JENNA BOROK AND LAWRENCE EICHENFIELD, MD

The scabies mite or the “itch mite” was discovered in 1687 as the first identifiable microorganism that caused human disease.1 Scabies is an infection of the epidermis with the mite, Sarcoptes scabiei variety hominis (S. scabiei) affecting approximately 300 million people worldwide.2 It is a common disease, especially among school-aged children and is particularly rampant in areas of poor sanitation and overcrowding.2,3

S. scabiei live in and on human skin where the impregnated female mite burrows into the stratum corneum and lays two to three eggs daily for as long as 30 days.3,4 The egg becomes a larva, which leaves the burrow and molts into a nymph, and it continues to molt into a mature mite.3 Mating then occurs during the mite stage. After mating, the male mite dies and the female completes the life cycle by burrowing back into the stratum corneum; this process takes about 2 weeks.3,4

Diagnosis

The diagnosis is usually based on strong clinical suspicion. The chief complaint is often a generalized itching rash that is often worse at nighttime.3,6 Small inflammatory papules are the main physical exam finding, and they usually are widely distributed, the favored locations including the finger webs, wrists, elbows, axillae, girdle area, and feet.3 In addition, male genitalia oftentimes are involved, and small itching papules on the penis should be considered scabies until proven otherwise.3 The head almost always is spared except in infants, who may present with pustules on the palms and soles of the feet and vesicles or lesions on the neck and face.7

The pathognomonic exam finding is the mite’s burrow, which appears as a 2-5 mm white, superficial, threadlike line. Upon close inspection, a tiny black speck often can be seen at the end of the burrow, which represents the adult mite.3 The presence of mites, eggs, or feces also is diagnostic and is accomplished by a skin scraping with a No. 15 blade.3 A positive scraping is diagnostic, although a negative scraping does not rule out the condition. (We explain this to our patients by saying “If you call someone’s home phone and they answer the phone, you know they are home. If you call and there is no answer, it could be that they aren’t home, or they are home and just not answering.”) A biopsy usually is not required, but may provide a diagnosis when scabies is unsuspected.3

The differential for red papules that itch in children includes atopic dermatitis, impetigo, papular urticaria, contact dermatitis, and other infestations, including bites from mosquitoes, fleas, and bed bugs. Atopic dermatitis (AD) can present as eczematous, erythematous papular lesions with oozing in flexural areas similar to areas affected by scabies. However, there are no burrows seen in AD, and the lesions are not in the interdigital web spaces. Impetigo has erythematous vesiculopustular lesions that form honey-colored crusts. Papular urticaria may be a hypersensitivity reaction to another insect, and the urticarial lesions are usually on the exposed parts of extremities. Unlike scabies, there are no burrows and usually no symptomatic family members. Contact dermatitis can present with vesicular, bullous, and sometimes papular erythematous lesions. It occurs after exposure to an allergen and often has well-demarcated borders with geometric shapes.

Treatment

Few randomized control or head-to-head trials exist on scabies treatment.2 First-line treatment is permethrin 5% cream, which is applied to the entire body surface from the neck down in children, but includes the face and scalp in infants.8,9 It is applied at bedtime and is washed off in the morning, and a second application is recommended after 7 days.3,8 It can be used in infants 2 months of age and older, and in pregnant females.3 Household contacts should be treated too, and those who are asymptomatic only require one application of permethrin.3 Permethrin is effective and more cost effective than ivermectin. Oral ivermectin has been used to treat scabies with a dose of 0.2 mg/kg and then repeated 2 weeks later, but the safety in children under 15 kg has not been determined.9 Lindane is an alternative option and is not recommended as first-line therapy because of its toxicity. It only should be used if the patient cannot tolerate or failed the previously mentioned therapies, with particular concern in children less than 50 kg.8,9 Infants and young children should be treated with permethrin and not with lindane.8 Clothes and bed linens can be decontaminated by machine-washing at a hot temperature.3,8 Topical corticosteroids and oral antihistamines can be helpful post-treatment to minimize pruritus and secondary eczematous changes.9

References

1. Int J Dermatol. 1998 Aug;37(8):625-30.

2. Interventions for treating scabies. The Cochrane database of systematic reviews. 2007. doi: 10.1002/14651858.CD000320.pub2.

3. Lookingbill and Marks’ Principles of Dermatology, 5th edition (Philadelphia: Elsevier, 2013).

4. BMJ. 2005 Sep 17;331(7517):619-22.

5. Br Med J. 1941 Sep 20;2(4211):405-6.

6. Lancet. 2006 May 27;367(9524):1767-74.

7. Am J Clin Dermatol. 2002;3(1):9-18.

8. MMWR June 5, 2015 / 64(RR3);1-137.

9. Scabies in Red Book: 2015 Report of the Committee on Infectious Diseases (Am Acad Pediatrics. 2015; pp. 702-4).

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Worker preparing drug
capsules for a clinical trial
Photo by Esther Dyson

Financial ties between principal investigators (PIs) and drug companies are independently associated with positive clinical trial results, according to new research.

The study showed a significant association between positive trial outcomes and PIs having financial ties to the manufacturer of the study drug, even after accounting for the source of research funding.

Researchers reported these findings in The BMJ.

Salomeh Keyhani, MD, of the University of California, San Francisco, and her colleagues conducted this research, analyzing a random sample of 195 drug trials published in 2013.

The team found financial ties between PIs and manufacturers of the study drug for 67.7% of the studies (n=132). In all, 58% of the PIs had financial ties to the manufacturers (231/397).

Types of financial ties included:

• Advisor/consultancy payments (39%)
• Speakers’ fees (20%)
• Unspecified financial ties (20%)
• Honoraria (13%)
• Employee relationships (13%)
• Travel fees (13%)
• Stock ownership (10%)
• Having a patent related to the study drug (5%).

PIs reported financial ties to the drug manufacturer in 76% (103/136) of studies with positive results and 49% (29/59) of studies with negative results (P<0.001).

In a multivariate analysis adjusted for the study’s funding source, a financial tie was significantly associated with a positive trial outcome. The odds ratio was 3.57 (P=0.001).

In a multivariate analysis adjusted for a range of other study-related factors as well, a financial tie remained significantly associated with a positive trial outcome. The odds ratio was 3.37 (P=0.006). 

Dr Keyhani and her colleagues stressed that this analysis was observational and cannot be used to draw conclusions about causation.

However, they said, given the importance of industry and academic collaboration in advancing the development of new treatments, “more thought needs to be given to the roles that investigators, policy makers, and journal editors can play in ensuring the credibility of the evidence base.”

Authors of a related editorial said more research is needed to determine how industry funding and financial ties could influence trial results.

The authors—Andreas Lundh, PhD, of the University of Southern Denmark, and Lisa Bero, PhD, of the University of Sydney in Australia—urged trial investigators to share their data and participate in industry-funded trials only if data are made publicly available.

The authors also suggested journals could help by rejecting research by investigators who are unwilling to share their data and by penalizing investigators who fail to disclose financial ties. The role of sponsors, or companies with which investigators have ties, in the research must also be transparent.

In the meantime, trials with industry funding or investigators with financial ties “should be interpreted with caution until all relevant information is fully disclosed and easily accessible,” the authors concluded.

Worker preparing drug
capsules for a clinical trial
Photo by Esther Dyson

Financial ties between principal investigators (PIs) and drug companies are independently associated with positive clinical trial results, according to new research.

The study showed a significant association between positive trial outcomes and PIs having financial ties to the manufacturer of the study drug, even after accounting for the source of research funding.

Researchers reported these findings in The BMJ.

Salomeh Keyhani, MD, of the University of California, San Francisco, and her colleagues conducted this research, analyzing a random sample of 195 drug trials published in 2013.

The team found financial ties between PIs and manufacturers of the study drug for 67.7% of the studies (n=132). In all, 58% of the PIs had financial ties to the manufacturers (231/397).

Types of financial ties included:

• Advisor/consultancy payments (39%)
• Speakers’ fees (20%)
• Unspecified financial ties (20%)
• Honoraria (13%)
• Employee relationships (13%)
• Travel fees (13%)
• Stock ownership (10%)
• Having a patent related to the study drug (5%).

PIs reported financial ties to the drug manufacturer in 76% (103/136) of studies with positive results and 49% (29/59) of studies with negative results (P<0.001).

In a multivariate analysis adjusted for the study’s funding source, a financial tie was significantly associated with a positive trial outcome. The odds ratio was 3.57 (P=0.001).

In a multivariate analysis adjusted for a range of other study-related factors as well, a financial tie remained significantly associated with a positive trial outcome. The odds ratio was 3.37 (P=0.006). 

Dr Keyhani and her colleagues stressed that this analysis was observational and cannot be used to draw conclusions about causation.

However, they said, given the importance of industry and academic collaboration in advancing the development of new treatments, “more thought needs to be given to the roles that investigators, policy makers, and journal editors can play in ensuring the credibility of the evidence base.”

Authors of a related editorial said more research is needed to determine how industry funding and financial ties could influence trial results.

The authors—Andreas Lundh, PhD, of the University of Southern Denmark, and Lisa Bero, PhD, of the University of Sydney in Australia—urged trial investigators to share their data and participate in industry-funded trials only if data are made publicly available.

The authors also suggested journals could help by rejecting research by investigators who are unwilling to share their data and by penalizing investigators who fail to disclose financial ties. The role of sponsors, or companies with which investigators have ties, in the research must also be transparent.

In the meantime, trials with industry funding or investigators with financial ties “should be interpreted with caution until all relevant information is fully disclosed and easily accessible,” the authors concluded.

Worker preparing drug
capsules for a clinical trial
Photo by Esther Dyson

Financial ties between principal investigators (PIs) and drug companies are independently associated with positive clinical trial results, according to new research.

The study showed a significant association between positive trial outcomes and PIs having financial ties to the manufacturer of the study drug, even after accounting for the source of research funding.

Researchers reported these findings in The BMJ.

Salomeh Keyhani, MD, of the University of California, San Francisco, and her colleagues conducted this research, analyzing a random sample of 195 drug trials published in 2013.

The team found financial ties between PIs and manufacturers of the study drug for 67.7% of the studies (n=132). In all, 58% of the PIs had financial ties to the manufacturers (231/397).

Types of financial ties included:

• Advisor/consultancy payments (39%)
• Speakers’ fees (20%)
• Unspecified financial ties (20%)
• Honoraria (13%)
• Employee relationships (13%)
• Travel fees (13%)
• Stock ownership (10%)
• Having a patent related to the study drug (5%).

PIs reported financial ties to the drug manufacturer in 76% (103/136) of studies with positive results and 49% (29/59) of studies with negative results (P<0.001).

In a multivariate analysis adjusted for the study’s funding source, a financial tie was significantly associated with a positive trial outcome. The odds ratio was 3.57 (P=0.001).

In a multivariate analysis adjusted for a range of other study-related factors as well, a financial tie remained significantly associated with a positive trial outcome. The odds ratio was 3.37 (P=0.006). 

Dr Keyhani and her colleagues stressed that this analysis was observational and cannot be used to draw conclusions about causation.

However, they said, given the importance of industry and academic collaboration in advancing the development of new treatments, “more thought needs to be given to the roles that investigators, policy makers, and journal editors can play in ensuring the credibility of the evidence base.”

Authors of a related editorial said more research is needed to determine how industry funding and financial ties could influence trial results.

The authors—Andreas Lundh, PhD, of the University of Southern Denmark, and Lisa Bero, PhD, of the University of Sydney in Australia—urged trial investigators to share their data and participate in industry-funded trials only if data are made publicly available.

The authors also suggested journals could help by rejecting research by investigators who are unwilling to share their data and by penalizing investigators who fail to disclose financial ties. The role of sponsors, or companies with which investigators have ties, in the research must also be transparent.

In the meantime, trials with industry funding or investigators with financial ties “should be interpreted with caution until all relevant information is fully disclosed and easily accessible,” the authors concluded.

Researcher examines
tumor in a test tube
Photo by Rhoda Baer

The US Department of Health and Human Services (HHS) and 15 other federal agencies have issued a final rule to update regulations intended to safeguard individuals who participate in research.

Most provisions in the new rule will go into effect in 2018.

The HHS says the new rule strengthens protections for people who volunteer to participate in research, while ensuring that the oversight system does not add inappropriate administrative burdens.

The current regulations, which have been in place since 1991, are often referred to as the “Common Rule.”

In September 2015, HHS and the other Common Rule agencies published a proposed new rule regarding research subjects—a notice of proposed rulemaking (NPRM)—which drew more than 2100 comments.

In response to concerns raised during the review process, the final rule contains a number of significant changes from the NPRM.

Research covered

The final rule does not cover clinical trials that are not federally funded.

The Common Rule has historically applied only to research conducted or supported by a Common Rule department or agency. And, although the NPRM proposed changing this policy, the final rule remains in line with the Common Rule.

Consent

The final rule requires consent forms to provide potential research subjects with a better understanding of a project’s scope so they can make a more fully informed decision about whether to participate.

Consent forms should include a concise explanation—at the beginning of the document—of the information that would be most important to individuals contemplating participation in a particular study, including the purpose of the research, the risks and benefits, and appropriate alternative treatments that might be beneficial to the prospective subject. 

The rule also requires that consent forms for certain federally funded clinical trials be posted on a public website.

Institutional review boards

The final rule requires, in many cases, use of a single institutional review board (IRB) for multi-institutional research studies.

However, the final rule has been modified from the NPRM to add substantial increased flexibility in now allowing broad groups of studies (instead of just specific studies) to be removed from this requirement.

Privacy

The final rule does not include the standardized privacy safeguards for identifiable private information and identifiable biospecimens that were proposed in the NPRM.

In most respects, the final rule retains the current approach to privacy standards.

For studies on stored identifiable data or identifiable biospecimens, researchers will have the option of relying on broad consent obtained for future research as an alternative to seeking IRB approval to waive the consent requirement.

As under the current rule, researchers will not have to obtain consent for studies on non-identified stored data or biospecimens.

Exemptions

The final rule establishes new exempt categories of research based on the level of risk they pose to participants.

For example, to reduce unnecessary regulatory burden and allow IRBs to focus their attention on higher-risk studies, there is a new exemption for secondary research involving identifiable private information if the research is regulated by and participants are protected under the HIPAA rules.

Review

The final rule removes the requirement to conduct continuing review of ongoing research studies in certain instances where such review does little to protect subjects.

For more details, see the final rule.

Researcher examines
tumor in a test tube
Photo by Rhoda Baer

The US Department of Health and Human Services (HHS) and 15 other federal agencies have issued a final rule to update regulations intended to safeguard individuals who participate in research.

Most provisions in the new rule will go into effect in 2018.

The HHS says the new rule strengthens protections for people who volunteer to participate in research, while ensuring that the oversight system does not add inappropriate administrative burdens.

The current regulations, which have been in place since 1991, are often referred to as the “Common Rule.”

In September 2015, HHS and the other Common Rule agencies published a proposed new rule regarding research subjects—a notice of proposed rulemaking (NPRM)—which drew more than 2100 comments.

In response to concerns raised during the review process, the final rule contains a number of significant changes from the NPRM.

Research covered

The final rule does not cover clinical trials that are not federally funded.

The Common Rule has historically applied only to research conducted or supported by a Common Rule department or agency. And, although the NPRM proposed changing this policy, the final rule remains in line with the Common Rule.

Consent

The final rule requires consent forms to provide potential research subjects with a better understanding of a project’s scope so they can make a more fully informed decision about whether to participate.

Consent forms should include a concise explanation—at the beginning of the document—of the information that would be most important to individuals contemplating participation in a particular study, including the purpose of the research, the risks and benefits, and appropriate alternative treatments that might be beneficial to the prospective subject. 

The rule also requires that consent forms for certain federally funded clinical trials be posted on a public website.

Institutional review boards

The final rule requires, in many cases, use of a single institutional review board (IRB) for multi-institutional research studies.

However, the final rule has been modified from the NPRM to add substantial increased flexibility in now allowing broad groups of studies (instead of just specific studies) to be removed from this requirement.

Privacy

The final rule does not include the standardized privacy safeguards for identifiable private information and identifiable biospecimens that were proposed in the NPRM.

In most respects, the final rule retains the current approach to privacy standards.

For studies on stored identifiable data or identifiable biospecimens, researchers will have the option of relying on broad consent obtained for future research as an alternative to seeking IRB approval to waive the consent requirement.

As under the current rule, researchers will not have to obtain consent for studies on non-identified stored data or biospecimens.

Exemptions

The final rule establishes new exempt categories of research based on the level of risk they pose to participants.

For example, to reduce unnecessary regulatory burden and allow IRBs to focus their attention on higher-risk studies, there is a new exemption for secondary research involving identifiable private information if the research is regulated by and participants are protected under the HIPAA rules.

Review

The final rule removes the requirement to conduct continuing review of ongoing research studies in certain instances where such review does little to protect subjects.

For more details, see the final rule.

Researcher examines
tumor in a test tube
Photo by Rhoda Baer

The US Department of Health and Human Services (HHS) and 15 other federal agencies have issued a final rule to update regulations intended to safeguard individuals who participate in research.

Most provisions in the new rule will go into effect in 2018.

The HHS says the new rule strengthens protections for people who volunteer to participate in research, while ensuring that the oversight system does not add inappropriate administrative burdens.

The current regulations, which have been in place since 1991, are often referred to as the “Common Rule.”

In September 2015, HHS and the other Common Rule agencies published a proposed new rule regarding research subjects—a notice of proposed rulemaking (NPRM)—which drew more than 2100 comments.

In response to concerns raised during the review process, the final rule contains a number of significant changes from the NPRM.

Research covered

The final rule does not cover clinical trials that are not federally funded.

The Common Rule has historically applied only to research conducted or supported by a Common Rule department or agency. And, although the NPRM proposed changing this policy, the final rule remains in line with the Common Rule.

Consent

The final rule requires consent forms to provide potential research subjects with a better understanding of a project’s scope so they can make a more fully informed decision about whether to participate.

Consent forms should include a concise explanation—at the beginning of the document—of the information that would be most important to individuals contemplating participation in a particular study, including the purpose of the research, the risks and benefits, and appropriate alternative treatments that might be beneficial to the prospective subject. 

The rule also requires that consent forms for certain federally funded clinical trials be posted on a public website.

Institutional review boards

The final rule requires, in many cases, use of a single institutional review board (IRB) for multi-institutional research studies.

However, the final rule has been modified from the NPRM to add substantial increased flexibility in now allowing broad groups of studies (instead of just specific studies) to be removed from this requirement.

Privacy

The final rule does not include the standardized privacy safeguards for identifiable private information and identifiable biospecimens that were proposed in the NPRM.

In most respects, the final rule retains the current approach to privacy standards.

For studies on stored identifiable data or identifiable biospecimens, researchers will have the option of relying on broad consent obtained for future research as an alternative to seeking IRB approval to waive the consent requirement.

As under the current rule, researchers will not have to obtain consent for studies on non-identified stored data or biospecimens.

Exemptions

The final rule establishes new exempt categories of research based on the level of risk they pose to participants.

For example, to reduce unnecessary regulatory burden and allow IRBs to focus their attention on higher-risk studies, there is a new exemption for secondary research involving identifiable private information if the research is regulated by and participants are protected under the HIPAA rules.

Review

The final rule removes the requirement to conduct continuing review of ongoing research studies in certain instances where such review does little to protect subjects.

For more details, see the final rule.

Colony of iPSCs
Photo from Salk Institute

Researchers have created an induced pluripotent stem cell (iPSC) library intended to aid the study of sickle cell disease (SCD).

The library consists of iPSCs generated from blood samples taken from ethnically diverse SCD patients from around the world.

The researchers say these iPSCs can be used to create disease models, which may allow scientists to better understand how SCD occurs and develop and test new treatments for the disease.

As a complement to the library, the researchers also designed CRISPR/Cas gene editing tools to correct the sickle hemoglobin mutation.

The team described this work in Stem Cell Reports.

“Sickle cell disease affects millions of people worldwide and is an emerging global health burden,” said study author George Murphy, PhD, of the Center for Regenerative Medicine at Boston University School of Medicine in Massachusetts.

“iPSCs have the potential to revolutionize the way we study human development, model life-threatening diseases, and, eventually, treat patients.”

The researchers’ library includes SCD-specific iPSCs from patients of different ethnicities with different β-globin gene haplotypes and fetal hemoglobin levels.

The researchers generated 54 iPSC lines from blood samples collected from individuals of African American, Brazilian, and Saudi Arabian descent. Both genders were represented, as well as a range of ages (3 to 53 years of age).

Most of the cell lines in the library, along with accompanying genetic and hematologic data, are freely available via the WiCell website.

“In addition to the library, we’ve designed and are using gene editing tools to correct the sickle hemoglobin mutation using the stem cell lines,” said Gustavo Mostoslavsky, MD, PhD, also of the Center for Regenerative Medicine at Boston University School of Medicine.

“When coupled with corrected sickle cell disease-specific iPSCs, these tools could one day provide a functional cure for the disorder.”

Colony of iPSCs
Photo from Salk Institute

Researchers have created an induced pluripotent stem cell (iPSC) library intended to aid the study of sickle cell disease (SCD).

The library consists of iPSCs generated from blood samples taken from ethnically diverse SCD patients from around the world.

The researchers say these iPSCs can be used to create disease models, which may allow scientists to better understand how SCD occurs and develop and test new treatments for the disease.

As a complement to the library, the researchers also designed CRISPR/Cas gene editing tools to correct the sickle hemoglobin mutation.

The team described this work in Stem Cell Reports.

“Sickle cell disease affects millions of people worldwide and is an emerging global health burden,” said study author George Murphy, PhD, of the Center for Regenerative Medicine at Boston University School of Medicine in Massachusetts.

“iPSCs have the potential to revolutionize the way we study human development, model life-threatening diseases, and, eventually, treat patients.”

The researchers’ library includes SCD-specific iPSCs from patients of different ethnicities with different β-globin gene haplotypes and fetal hemoglobin levels.

The researchers generated 54 iPSC lines from blood samples collected from individuals of African American, Brazilian, and Saudi Arabian descent. Both genders were represented, as well as a range of ages (3 to 53 years of age).

Most of the cell lines in the library, along with accompanying genetic and hematologic data, are freely available via the WiCell website.

“In addition to the library, we’ve designed and are using gene editing tools to correct the sickle hemoglobin mutation using the stem cell lines,” said Gustavo Mostoslavsky, MD, PhD, also of the Center for Regenerative Medicine at Boston University School of Medicine.

“When coupled with corrected sickle cell disease-specific iPSCs, these tools could one day provide a functional cure for the disorder.”

Colony of iPSCs
Photo from Salk Institute

Researchers have created an induced pluripotent stem cell (iPSC) library intended to aid the study of sickle cell disease (SCD).

The library consists of iPSCs generated from blood samples taken from ethnically diverse SCD patients from around the world.

The researchers say these iPSCs can be used to create disease models, which may allow scientists to better understand how SCD occurs and develop and test new treatments for the disease.

As a complement to the library, the researchers also designed CRISPR/Cas gene editing tools to correct the sickle hemoglobin mutation.

The team described this work in Stem Cell Reports.

“Sickle cell disease affects millions of people worldwide and is an emerging global health burden,” said study author George Murphy, PhD, of the Center for Regenerative Medicine at Boston University School of Medicine in Massachusetts.

“iPSCs have the potential to revolutionize the way we study human development, model life-threatening diseases, and, eventually, treat patients.”

The researchers’ library includes SCD-specific iPSCs from patients of different ethnicities with different β-globin gene haplotypes and fetal hemoglobin levels.

The researchers generated 54 iPSC lines from blood samples collected from individuals of African American, Brazilian, and Saudi Arabian descent. Both genders were represented, as well as a range of ages (3 to 53 years of age).

Most of the cell lines in the library, along with accompanying genetic and hematologic data, are freely available via the WiCell website.

“In addition to the library, we’ve designed and are using gene editing tools to correct the sickle hemoglobin mutation using the stem cell lines,” said Gustavo Mostoslavsky, MD, PhD, also of the Center for Regenerative Medicine at Boston University School of Medicine.

“When coupled with corrected sickle cell disease-specific iPSCs, these tools could one day provide a functional cure for the disorder.”

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.

Coronary-subclavian steal syndrome (CSSS) is a rare clinical entity with an incidence of 0.2% to 0.7%.¹ Despite its scarcity, CSSS is a condition that can result in devastating clinical consequences, such as myocardial ischemia, ranging from angina to myocardial infarction (MI) and ischemic cardiomyopathy.²

In 1974, Harjola and Valle first reported the angiographic and physiologic descriptions of CSSS in an asymptomatic patient who was found to have flow reversal in the left internal mammary artery (LIMA) graft in a follow-up coronary angiography performed 11 months after coronary artery bypass grafting (CABG).³ Because of the similarity in the pathophysiology of this condition with vertebral-subclavian steal syndrome, this clinical entity was named coronary-subclavian steal syndrome (CSSS).^4,5

In steal-syndrome phenomena, there is a significant stenosis in the subclavian artery proximal to the origin of an arterial branch, either LIMA or vertebral artery, resulting in lower pressure in the distal subclavian artery. As a result, the negative pressure gradient might be sufficient to cause retrograde flow; consequently causing arterial branch “flow reversal,” and then “steal” flow from the organ—either heart or brain—supplied by that artery.^3,6

Coronary-subclavian steal syndrome is caused by a reversal of flow in a previously constructed internal mammary artery (IMA)-coronary conduit graft. It typically results from hemodynamically significant subclavian artery stenosis proximal to the ipsilateral IMA. The reversal of flow will “steal” the blood from the coronary territory supplied by the IMA conduit.^4,5 The absence of proximal subclavian artery stenosis does not preclude the presence of this syndrome; reversal in the IMA conduit can occur in association with upper extremity hemodialysis fistulae or anomalous connection of the left subclavian artery to the pulmonary artery in d-transposition of the great arteries.² Although the stenosis is most commonly caused by atherosclerotic disease, other clinical entities, including Takayasu vasculitis, radiation, and giant cell arteritis, have been described.⁶ Patients with CSSS usually present with stable or unstable angina as well as arm claudication and various neurologic symptoms.⁵ The consequence of CSSS can include ischemic cardiomyopathy, acute MI,⁷ stroke, and death.^5,8

Case Presentation

A 66-year-old man with a previous MI managed with CABG, permanent atrial fibrillation (AF), and moderate aortic stenosis presented to the ambulatory clinic with recurrent symptoms of stable angina despite being on maximal anti-anginal therapy. A coronary angiogram performed 4 years earlier had revealed significant left main artery disease and total occlusion of the right coronary artery.

Cardiovascular examination revealed an irregular rhythm with a normal S1, variable S2, and a 3/6 systolic ejection murmur heard best at the right second intercostal space with radiation to the carotids. His peripheral pulses were equal and symmetric in the lower extremities, and no peripheral edema was noted. The remainder of the physical examination was otherwise unremarkable. The resting 12-lead electrocardiogram showed AF at a rate of 60 bpm (Figure 1).

A stress test was performed to elucidate a possible coronary distribution for the cause of the chest pain.

Consequently, coronary angiography was performed and showed 95% left main stenosis and total occlusion of the mid-right coronary artery with right dominance, patent LIMA to mid-LAD and patent saphenous venous graft to posterior descending artery grafts (Figure 3)

The patient underwent percutaneous transluminal angioplasty (PTA) of the subclavian stenosis with insertion of an 8 mm x 27 mm balloon-expandable peripheral stent (Figure 5) (Supplemental video 6). The patient tolerated the procedure well without complications and with resolution of his symptoms at a 6-month follow-up.

Discussion

Long-term follow-up of LIMA as a conduit to LAD has shown a 10-year patency of 95% compared with 76% for saphenous vein and an associated 10-year survival of 93.4% for LIMA compared with 88% for saphenous vein graft.^9,10 Because of the superiority of LIMA outcomes, it has become the preferred graft in CABG. However, this approach is associated with 0.1% to 0.2% risk of ischemia related to flow reversal in the LIMA b

Greater awareness and improvement in diagnostic imaging have contributed to the increased incidence of CSSS and its consequences.² Although symptoms related to myocardial ischemia, as in this case, are the most dominant in CSSS, other brachiocephalic symptoms, including vertebral-subclavian steal, transient ischemic attacks, and strokes, have been reported.¹¹ Additionally, the same disease might compromise distal flow, resulting in extremity claudication or even distal microembolization.¹²

It is important to recognize that significant brachiocephalic stenosis has been reported in about 0.2% to 2.5% of patients undergoing elective CABG.^6,8 Therefore, it is essential to screen for brachiocephalic artery disease before undergoing CABG. Different strategies have been suggested, including assessing pressure gradient between the upper extremities as the initial step; CSSS should be considered when the pressure gradient is > 20 mm Hg.

Other strategies include ultrasonic duplex scanning with provocation test using arm exercise or reactive hyperemia.¹³ Many high-volume centers are performing screening by proximal subclavian angiography in all patients undergoing coronary angiography. When significant disease is detected, arch aortography and 4-vessel cerebral angiography is performed.⁶ In addition, other centers have adopted the routine use of computerized tomographic angiography before CABG.¹⁴

Surgical correction of CSSS is considered to be the gold standard and can be accomplished by performing aorta-subclavian bypass, carotid-subclavian bypass, axillo-axillary bypass, or relocation of the IMA graft.² Although this approach is invasive and carries many disadvantages related to patient comfort,surgical revascularization can be performed safely at the time of CABG and may not carry additional risk of morbidity or mortality.¹⁵ Moreover, surgical correction is the preferred modality for treatment of CSSS when the anatomy is not favorable for percutaneous intervention, such as chronic total occlusion of the subclavian artery.¹⁵Alternatively, CSSS can effectively be managed less invasively by percutaneous intervention, including PTA with stent placement,^16,17 thrombectomy¹⁸ or atherectomy of the stenotic subclavian artery.¹⁹

In this patient, PTA was performed with primary stent placement. The lesion was crossed with a sheath, using combined femoral and radial access. After proper positioning, a balloon-expandable stent was deployed that resulted in complete angiographic resolution of the lesion and improvement of symptoms at 6-month follow-up. In line with previous reports, this case demonstrated that percutaneous intervention is a feasible and less invasive approach for management of CSSS.^16,17 The effectiveness of the percutaneous approach has effectiveness equivalent to surgical bypass with minimal complications and good long-term success. Therefore, it has been suggested as first-line therapy in CSSS.^8,16

Although preoperative screening for brachiocephalic disease before undergoing ipsilateral IMA coronary artery bypass can prevent the development of CSSS, there is controversy about the best approach for managing these concomitant conditions. Many institutions use all-vein coronary conduits, but that forgoes the benefit of a LIMA graft. Therefore, others still perform an IMA conduit after brachiocephalic reconstruction. An alternative method is to use free IMA or radial artery conduit. Currently, there are limited data about the use of endovascular treatment for brachiocephalic disease with a CABG.²

Conclusion

Coronary-subclavian steal syndrome is an important clinical condition that is associated with significant morbidity and mortality. In the Sullivan and colleagues report of 27 patients with CSSS, 59.3% had stable angina and 40.7% had acute coronary syndrome, among which 14.8% presented with acute MI.⁷ Therefore, early recognition is essential to prevent catastrophic consequences.

Patients with CSSS usually present with cardiac symptoms, but symptoms related to vertebral-subclavian steal and posterior cerebral insufficiency can coexist. The authors suggest routine preoperative screening for the presence of brachiocephalic disease, using ultrasonic duplex or angiography. This practice is cost-effective and essential to prevent the development of CSSS. Optimal management of brachiocephalic disease prior to CABG is debatable; however, IMA grafting and reconstruction of the brachiocephalic system seems to be a promising approach.

When CSSS develops after CABG, the condition can be successfully treated with percutaneous intervention and outcomes comparable with those of surgical bypass.

Acknowledgments
Special thanks to the division of cardiology at New Jersey VA Health Care System, in particular Steve Tsai, MD; Ronald L. Vaillancourt, RN, and Preciosa Yap, RN.