NEWPORT BEACH, CALIF. – For decades, hidradenitis suppurativa (HS) has been characterized as a rare disorder, but recent evidence from the medical dermatology literature suggests that between 0.4% and 4% of the population is affected, with a predominance in female and black individuals.

At the annual meeting of the Pacific Dermatologic Association, Haley Naik, MD, characterized those estimates as “astounding.” There is also diagnostic delay that ranges from 5 to 14 years in Western populations, said Dr. Naik, of the department of dermatology at the University of California, San Francisco (Br J Dermatol. 2015 Dec;173[6]:1546-9). “These patients are repeatedly interacting with the health care system and they’re not getting the correct diagnosis and therefore they’re not getting effective therapy for the management of their disease,” she said. “We can begin to tackle this problem by educating ourselves and our colleagues about the best ways to diagnose these patients.”

In 2015, a group of European researchers published proposed diagnostic criteria for hidradenitis suppurativa (Dermatology. 2015;231[2]:184-90). The criteria comprise three components: typical lesions (double-ended comedones, active inflammatory cysts and nodules, abscesses, follicularly-based papules and pustules, fistula and sinus formation, and scarring); typical distribution (in intertriginous areas such as the axilla and the buttocks), and chronicity (they suggest that patients must have at least two episodes of the disease over a 6-month period). “In addition to satisfying these three criteria, they also suggest that there are some secondary criteria that can be used to help make this diagnosis: a family history of [hidradenitis suppurativa] and absence of pathogens at lesional sites,” Dr. Naik said. “These criteria are a practical framework in which we can begin to educate our colleagues about this diagnosis, but they should not lead us to believe that hidradenitis suppurativa is a phenotypically homogenous disease.”

There are multiple phenotypes of HS, including comedonal, nodular/cystic, and ulcerative. Typical sites that are involved are the axilla, groin, and buttocks. “There is also a subset of patients who are typically thin and male who have a gluteal predominant, or exclusive presentation of their disease,” Dr. Naik said. “In my experience, these patients tend to have severe and progressive disease.” Atypical sites include the postauricular skin, the trunk, and the extremities.

In a cross-sectional study, researchers in France found that HS patients fall into one of three categories. Those in category 1 had involvement of breasts, axilla, and hypertrophic scars; those in category 2 had involvement of the breasts, axilla, ears, chest, back, follicular lesions, and acne, and tended to have a family history of HS; those in category 3 had gluteal involvement with prominent papules and folliculitis (J Invest Dermatol. 2013 Jun;133[6]:1506-11). “Ideally, we hope this type of phenotyping will facilitate phenotype-genotype correlation, and eventually help in understanding disease course of these patients leading to optimized therapeutic options,” Dr. Naik said. “We’re just at the tip of the iceberg here in learning about these various disease subtypes.”

In 2015, the tumor necrosis factor blocker adalimumab (Humira) became the first treatment approved by the Food and Drug Administration for HS, for moderate to severe disease in adults. “The problem is, the dosing and the dose frequency of adalimumab is fixed, so if your patient is only partially responding to the therapy, you don’t have much wiggle room in terms of trying to titrate this medication,” Dr. Naik said. “In that situation the agent of choice to switch to is infliximab.”

Another biologic agent, the interleukin-1 receptor antagonist anakinra (Kineret), also shows promise. Results from a small randomized study of 20 patients found that 7 of 10 patients in the treatment group reported 80% improvement in their disease, compared with 3 out of 10 in the placebo group (JAMA Dermatol. 2016;152[1]:52-9). “Further work needs to be done in this area to understand the efficacy of anakinra for HS,” she said. “I certainly wouldn’t consider anakinra a first- or second-line therapy for the management of HS, but it’s an option for patients who have refractory disease.”

In addition to experiencing fistula and sinus formation, scarring, and wound contractures, HS patients are at risk for developing a host of complications, including lymphedema, peripheral neuropathy, squamous cell carcinoma, chronic pain, anemia, hypoproteinemia, amyloidosis, nephrotic syndrome, and uveitis. According to Dr. Naik, surgical management of HS can be considered in patients who have localized severe disease in which the risks of long-term immunosuppressive therapy outweigh the benefits. “In patients who have chronic refractory disease, surgical management can be particularly helpful,” she said. “In those who have fistula or sinus formation, significant scarring, or range of motion limitation from wound contractures, medical management can only go so far, because the medication can’t really get to those areas.”

Dr. Naik concluded her presentation by emphasizing the role dermatologists can play in helping patients address comorbidities that can accompany HS, from obesity and lipid abnormalities, to depression and arthritis. “We as dermatologists may not be in a position to manage these patients’ comorbidities over the long term, but we are in a position to encourage them to seek additional medical attention and to communicate with our colleagues when appropriate to help facilitate multidisciplinary management of this disease,” she said. “I routinely pull on the sleeves of my surgical and medical colleagues to get help with my most complicated HS patients.”

Dr. Naik reported having no financial disclosures.

dbrunk@frontlinemedcom.com

NEWPORT BEACH, CALIF. – For decades, hidradenitis suppurativa (HS) has been characterized as a rare disorder, but recent evidence from the medical dermatology literature suggests that between 0.4% and 4% of the population is affected, with a predominance in female and black individuals.

At the annual meeting of the Pacific Dermatologic Association, Haley Naik, MD, characterized those estimates as “astounding.” There is also diagnostic delay that ranges from 5 to 14 years in Western populations, said Dr. Naik, of the department of dermatology at the University of California, San Francisco (Br J Dermatol. 2015 Dec;173[6]:1546-9). “These patients are repeatedly interacting with the health care system and they’re not getting the correct diagnosis and therefore they’re not getting effective therapy for the management of their disease,” she said. “We can begin to tackle this problem by educating ourselves and our colleagues about the best ways to diagnose these patients.”

In 2015, a group of European researchers published proposed diagnostic criteria for hidradenitis suppurativa (Dermatology. 2015;231[2]:184-90). The criteria comprise three components: typical lesions (double-ended comedones, active inflammatory cysts and nodules, abscesses, follicularly-based papules and pustules, fistula and sinus formation, and scarring); typical distribution (in intertriginous areas such as the axilla and the buttocks), and chronicity (they suggest that patients must have at least two episodes of the disease over a 6-month period). “In addition to satisfying these three criteria, they also suggest that there are some secondary criteria that can be used to help make this diagnosis: a family history of [hidradenitis suppurativa] and absence of pathogens at lesional sites,” Dr. Naik said. “These criteria are a practical framework in which we can begin to educate our colleagues about this diagnosis, but they should not lead us to believe that hidradenitis suppurativa is a phenotypically homogenous disease.”

There are multiple phenotypes of HS, including comedonal, nodular/cystic, and ulcerative. Typical sites that are involved are the axilla, groin, and buttocks. “There is also a subset of patients who are typically thin and male who have a gluteal predominant, or exclusive presentation of their disease,” Dr. Naik said. “In my experience, these patients tend to have severe and progressive disease.” Atypical sites include the postauricular skin, the trunk, and the extremities.

In a cross-sectional study, researchers in France found that HS patients fall into one of three categories. Those in category 1 had involvement of breasts, axilla, and hypertrophic scars; those in category 2 had involvement of the breasts, axilla, ears, chest, back, follicular lesions, and acne, and tended to have a family history of HS; those in category 3 had gluteal involvement with prominent papules and folliculitis (J Invest Dermatol. 2013 Jun;133[6]:1506-11). “Ideally, we hope this type of phenotyping will facilitate phenotype-genotype correlation, and eventually help in understanding disease course of these patients leading to optimized therapeutic options,” Dr. Naik said. “We’re just at the tip of the iceberg here in learning about these various disease subtypes.”

In 2015, the tumor necrosis factor blocker adalimumab (Humira) became the first treatment approved by the Food and Drug Administration for HS, for moderate to severe disease in adults. “The problem is, the dosing and the dose frequency of adalimumab is fixed, so if your patient is only partially responding to the therapy, you don’t have much wiggle room in terms of trying to titrate this medication,” Dr. Naik said. “In that situation the agent of choice to switch to is infliximab.”

Another biologic agent, the interleukin-1 receptor antagonist anakinra (Kineret), also shows promise. Results from a small randomized study of 20 patients found that 7 of 10 patients in the treatment group reported 80% improvement in their disease, compared with 3 out of 10 in the placebo group (JAMA Dermatol. 2016;152[1]:52-9). “Further work needs to be done in this area to understand the efficacy of anakinra for HS,” she said. “I certainly wouldn’t consider anakinra a first- or second-line therapy for the management of HS, but it’s an option for patients who have refractory disease.”

In addition to experiencing fistula and sinus formation, scarring, and wound contractures, HS patients are at risk for developing a host of complications, including lymphedema, peripheral neuropathy, squamous cell carcinoma, chronic pain, anemia, hypoproteinemia, amyloidosis, nephrotic syndrome, and uveitis. According to Dr. Naik, surgical management of HS can be considered in patients who have localized severe disease in which the risks of long-term immunosuppressive therapy outweigh the benefits. “In patients who have chronic refractory disease, surgical management can be particularly helpful,” she said. “In those who have fistula or sinus formation, significant scarring, or range of motion limitation from wound contractures, medical management can only go so far, because the medication can’t really get to those areas.”

Dr. Naik concluded her presentation by emphasizing the role dermatologists can play in helping patients address comorbidities that can accompany HS, from obesity and lipid abnormalities, to depression and arthritis. “We as dermatologists may not be in a position to manage these patients’ comorbidities over the long term, but we are in a position to encourage them to seek additional medical attention and to communicate with our colleagues when appropriate to help facilitate multidisciplinary management of this disease,” she said. “I routinely pull on the sleeves of my surgical and medical colleagues to get help with my most complicated HS patients.”

Dr. Naik reported having no financial disclosures.

dbrunk@frontlinemedcom.com

NEWPORT BEACH, CALIF. – For decades, hidradenitis suppurativa (HS) has been characterized as a rare disorder, but recent evidence from the medical dermatology literature suggests that between 0.4% and 4% of the population is affected, with a predominance in female and black individuals.

At the annual meeting of the Pacific Dermatologic Association, Haley Naik, MD, characterized those estimates as “astounding.” There is also diagnostic delay that ranges from 5 to 14 years in Western populations, said Dr. Naik, of the department of dermatology at the University of California, San Francisco (Br J Dermatol. 2015 Dec;173[6]:1546-9). “These patients are repeatedly interacting with the health care system and they’re not getting the correct diagnosis and therefore they’re not getting effective therapy for the management of their disease,” she said. “We can begin to tackle this problem by educating ourselves and our colleagues about the best ways to diagnose these patients.”

In 2015, a group of European researchers published proposed diagnostic criteria for hidradenitis suppurativa (Dermatology. 2015;231[2]:184-90). The criteria comprise three components: typical lesions (double-ended comedones, active inflammatory cysts and nodules, abscesses, follicularly-based papules and pustules, fistula and sinus formation, and scarring); typical distribution (in intertriginous areas such as the axilla and the buttocks), and chronicity (they suggest that patients must have at least two episodes of the disease over a 6-month period). “In addition to satisfying these three criteria, they also suggest that there are some secondary criteria that can be used to help make this diagnosis: a family history of [hidradenitis suppurativa] and absence of pathogens at lesional sites,” Dr. Naik said. “These criteria are a practical framework in which we can begin to educate our colleagues about this diagnosis, but they should not lead us to believe that hidradenitis suppurativa is a phenotypically homogenous disease.”

There are multiple phenotypes of HS, including comedonal, nodular/cystic, and ulcerative. Typical sites that are involved are the axilla, groin, and buttocks. “There is also a subset of patients who are typically thin and male who have a gluteal predominant, or exclusive presentation of their disease,” Dr. Naik said. “In my experience, these patients tend to have severe and progressive disease.” Atypical sites include the postauricular skin, the trunk, and the extremities.

In a cross-sectional study, researchers in France found that HS patients fall into one of three categories. Those in category 1 had involvement of breasts, axilla, and hypertrophic scars; those in category 2 had involvement of the breasts, axilla, ears, chest, back, follicular lesions, and acne, and tended to have a family history of HS; those in category 3 had gluteal involvement with prominent papules and folliculitis (J Invest Dermatol. 2013 Jun;133[6]:1506-11). “Ideally, we hope this type of phenotyping will facilitate phenotype-genotype correlation, and eventually help in understanding disease course of these patients leading to optimized therapeutic options,” Dr. Naik said. “We’re just at the tip of the iceberg here in learning about these various disease subtypes.”

In 2015, the tumor necrosis factor blocker adalimumab (Humira) became the first treatment approved by the Food and Drug Administration for HS, for moderate to severe disease in adults. “The problem is, the dosing and the dose frequency of adalimumab is fixed, so if your patient is only partially responding to the therapy, you don’t have much wiggle room in terms of trying to titrate this medication,” Dr. Naik said. “In that situation the agent of choice to switch to is infliximab.”

Another biologic agent, the interleukin-1 receptor antagonist anakinra (Kineret), also shows promise. Results from a small randomized study of 20 patients found that 7 of 10 patients in the treatment group reported 80% improvement in their disease, compared with 3 out of 10 in the placebo group (JAMA Dermatol. 2016;152[1]:52-9). “Further work needs to be done in this area to understand the efficacy of anakinra for HS,” she said. “I certainly wouldn’t consider anakinra a first- or second-line therapy for the management of HS, but it’s an option for patients who have refractory disease.”

In addition to experiencing fistula and sinus formation, scarring, and wound contractures, HS patients are at risk for developing a host of complications, including lymphedema, peripheral neuropathy, squamous cell carcinoma, chronic pain, anemia, hypoproteinemia, amyloidosis, nephrotic syndrome, and uveitis. According to Dr. Naik, surgical management of HS can be considered in patients who have localized severe disease in which the risks of long-term immunosuppressive therapy outweigh the benefits. “In patients who have chronic refractory disease, surgical management can be particularly helpful,” she said. “In those who have fistula or sinus formation, significant scarring, or range of motion limitation from wound contractures, medical management can only go so far, because the medication can’t really get to those areas.”

Dr. Naik concluded her presentation by emphasizing the role dermatologists can play in helping patients address comorbidities that can accompany HS, from obesity and lipid abnormalities, to depression and arthritis. “We as dermatologists may not be in a position to manage these patients’ comorbidities over the long term, but we are in a position to encourage them to seek additional medical attention and to communicate with our colleagues when appropriate to help facilitate multidisciplinary management of this disease,” she said. “I routinely pull on the sleeves of my surgical and medical colleagues to get help with my most complicated HS patients.”

Dr. Naik reported having no financial disclosures.

dbrunk@frontlinemedcom.com

New anticancer drugs are often expensive and have been accompanied by large increases in the cost of medical treatment, but they also are associated with gains in life expectancy, according to an analysis of Medicare data published online.

Investigators looked at four different types of cancer – breast, kidney, lung, and chronic myeloid leukemia (CML) – over two time periods: 1996-2000 and 2007-2011. Patients treated for CML during 2007-2011 had the largest increases in both average lifetime medical cost ($142,000) and months of life gained (22.1) over those treated during 1996-2000, reported David H. Howard, PhD, of Emory University, Atlanta, and his associates.

Breast cancer patients had the next-largest increases: 13.2 months of life expectancy and $72,000 in lifetime medical cost for those who received physician-administered intravenous drugs. For breast cancer patients who received only oral drugs, the increases were 2 months of life and $9,000 in lifetime cost, they noted.

Patients with kidney cancer had an average life-expectancy increase of 7.9 months and a cost increase of $45,000, but those estimates don’t fully reflect the effect of several oral drugs that were introduced after 2007 but did not come into widespread use during the entire study period, Dr. Howard and his associates noted (Health Aff. 2016 Sep 7;35[9]:1581-7).

Lung cancer patients experienced the smallest changes between the two time periods, with an increase in life expectancy of 3.9 months for those who received physician-administered anticancer drugs and a lifetime medical cost increase of $23,000. Patients with lung cancer who did not receive such drugs had increases of 0.7 months of life expectancy and $4,000 in lifetime medical costs.

The researchers used data from the Surveillance, Epidemiology, and End Results–Medicare database, and all costs are adjusted to 2012 dollars. Data collection was supported by the California Department of Health and funding for the study was provided by Pfizer. Three of Dr. Howard’s five coinvestigators are Pfizer employees.

rfranki@frontlinemedcom.com

New anticancer drugs are often expensive and have been accompanied by large increases in the cost of medical treatment, but they also are associated with gains in life expectancy, according to an analysis of Medicare data published online.

Investigators looked at four different types of cancer – breast, kidney, lung, and chronic myeloid leukemia (CML) – over two time periods: 1996-2000 and 2007-2011. Patients treated for CML during 2007-2011 had the largest increases in both average lifetime medical cost ($142,000) and months of life gained (22.1) over those treated during 1996-2000, reported David H. Howard, PhD, of Emory University, Atlanta, and his associates.

Breast cancer patients had the next-largest increases: 13.2 months of life expectancy and $72,000 in lifetime medical cost for those who received physician-administered intravenous drugs. For breast cancer patients who received only oral drugs, the increases were 2 months of life and $9,000 in lifetime cost, they noted.

Patients with kidney cancer had an average life-expectancy increase of 7.9 months and a cost increase of $45,000, but those estimates don’t fully reflect the effect of several oral drugs that were introduced after 2007 but did not come into widespread use during the entire study period, Dr. Howard and his associates noted (Health Aff. 2016 Sep 7;35[9]:1581-7).

Lung cancer patients experienced the smallest changes between the two time periods, with an increase in life expectancy of 3.9 months for those who received physician-administered anticancer drugs and a lifetime medical cost increase of $23,000. Patients with lung cancer who did not receive such drugs had increases of 0.7 months of life expectancy and $4,000 in lifetime medical costs.

The researchers used data from the Surveillance, Epidemiology, and End Results–Medicare database, and all costs are adjusted to 2012 dollars. Data collection was supported by the California Department of Health and funding for the study was provided by Pfizer. Three of Dr. Howard’s five coinvestigators are Pfizer employees.

rfranki@frontlinemedcom.com

New anticancer drugs are often expensive and have been accompanied by large increases in the cost of medical treatment, but they also are associated with gains in life expectancy, according to an analysis of Medicare data published online.

Investigators looked at four different types of cancer – breast, kidney, lung, and chronic myeloid leukemia (CML) – over two time periods: 1996-2000 and 2007-2011. Patients treated for CML during 2007-2011 had the largest increases in both average lifetime medical cost ($142,000) and months of life gained (22.1) over those treated during 1996-2000, reported David H. Howard, PhD, of Emory University, Atlanta, and his associates.

Breast cancer patients had the next-largest increases: 13.2 months of life expectancy and $72,000 in lifetime medical cost for those who received physician-administered intravenous drugs. For breast cancer patients who received only oral drugs, the increases were 2 months of life and $9,000 in lifetime cost, they noted.

Patients with kidney cancer had an average life-expectancy increase of 7.9 months and a cost increase of $45,000, but those estimates don’t fully reflect the effect of several oral drugs that were introduced after 2007 but did not come into widespread use during the entire study period, Dr. Howard and his associates noted (Health Aff. 2016 Sep 7;35[9]:1581-7).

Lung cancer patients experienced the smallest changes between the two time periods, with an increase in life expectancy of 3.9 months for those who received physician-administered anticancer drugs and a lifetime medical cost increase of $23,000. Patients with lung cancer who did not receive such drugs had increases of 0.7 months of life expectancy and $4,000 in lifetime medical costs.

The researchers used data from the Surveillance, Epidemiology, and End Results–Medicare database, and all costs are adjusted to 2012 dollars. Data collection was supported by the California Department of Health and funding for the study was provided by Pfizer. Three of Dr. Howard’s five coinvestigators are Pfizer employees.

rfranki@frontlinemedcom.com

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

SVS member Dr. Spence M. Taylor has been elected vice chair of the American Board of Surgery for 2017-18. He will serve as chair in 2018-19. Dr. Taylor joined the ABS as a director in 2011, representing the Southern Surgical Association.

He is a member of the ABS Vascular Surgery Board and Credentials Committee.

For more information, read the ABS summer newsletter.

SVS member Dr. Spence M. Taylor has been elected vice chair of the American Board of Surgery for 2017-18. He will serve as chair in 2018-19. Dr. Taylor joined the ABS as a director in 2011, representing the Southern Surgical Association.

He is a member of the ABS Vascular Surgery Board and Credentials Committee.

For more information, read the ABS summer newsletter.

SVS member Dr. Spence M. Taylor has been elected vice chair of the American Board of Surgery for 2017-18. He will serve as chair in 2018-19. Dr. Taylor joined the ABS as a director in 2011, representing the Southern Surgical Association.

He is a member of the ABS Vascular Surgery Board and Credentials Committee.

For more information, read the ABS summer newsletter.

All SVS members may submit proposals for invited sessions for the 2017 Vascular Annual Meeting, set for May 31 to June 3 (plenaries and exhibits are June 1 to 3) in San Diego, Calif.

Previously, the process was open only to SVS committees; planners opened the process to all members this year, with any and all ideas for sessions to be reviewed for further development.

Invited sessions include postgraduate courses, breakfast and concurrent sessions and workshops. Initial submissions are due Sept. 16.

Learn more here.

All SVS members may submit proposals for invited sessions for the 2017 Vascular Annual Meeting, set for May 31 to June 3 (plenaries and exhibits are June 1 to 3) in San Diego, Calif.

Previously, the process was open only to SVS committees; planners opened the process to all members this year, with any and all ideas for sessions to be reviewed for further development.

Invited sessions include postgraduate courses, breakfast and concurrent sessions and workshops. Initial submissions are due Sept. 16.

Learn more here.

All SVS members may submit proposals for invited sessions for the 2017 Vascular Annual Meeting, set for May 31 to June 3 (plenaries and exhibits are June 1 to 3) in San Diego, Calif.

Previously, the process was open only to SVS committees; planners opened the process to all members this year, with any and all ideas for sessions to be reviewed for further development.

Invited sessions include postgraduate courses, breakfast and concurrent sessions and workshops. Initial submissions are due Sept. 16.

Learn more here.

Just in time for the September recertification exam! Recordings of the 2015 Comprehensive Vascular Review Course are available for purchase. The 2015 intensive two-day course was led by vascular surgeons with extensive expertise in their respective fields.

The recordings include didactic lectures and review of essential VESAP questions. The recordings also provide a comprehensive update in all areas of vascular surgery.

No CME credit is available.

Purchase the recordings here.

Just in time for the September recertification exam! Recordings of the 2015 Comprehensive Vascular Review Course are available for purchase. The 2015 intensive two-day course was led by vascular surgeons with extensive expertise in their respective fields.

The recordings include didactic lectures and review of essential VESAP questions. The recordings also provide a comprehensive update in all areas of vascular surgery.

No CME credit is available.

Purchase the recordings here.

Just in time for the September recertification exam! Recordings of the 2015 Comprehensive Vascular Review Course are available for purchase. The 2015 intensive two-day course was led by vascular surgeons with extensive expertise in their respective fields.

The recordings include didactic lectures and review of essential VESAP questions. The recordings also provide a comprehensive update in all areas of vascular surgery.

No CME credit is available.

Purchase the recordings here.

SVS members who are researchers and clinicians have an opportunity to win $5,000 for study hypotheses in cardiovascular research.

The American Heart Association and PCORI (Patient-Centered Outcomes Research Institute) have announced a ‘crowdsourcing’ challenge, asking researchers and clinicians to suggest research questions that address difficult challenges identified by patients with cardiovascular diseases. Proposals should focus on questions that can be answered through comparative clinical effectiveness research with a precision medicine approach.

Submissions are due by Oct. 6. Four winners will each receive a $5,000 cash prize.

SVS members who are researchers and clinicians have an opportunity to win $5,000 for study hypotheses in cardiovascular research.

The American Heart Association and PCORI (Patient-Centered Outcomes Research Institute) have announced a ‘crowdsourcing’ challenge, asking researchers and clinicians to suggest research questions that address difficult challenges identified by patients with cardiovascular diseases. Proposals should focus on questions that can be answered through comparative clinical effectiveness research with a precision medicine approach.

Submissions are due by Oct. 6. Four winners will each receive a $5,000 cash prize.

SVS members who are researchers and clinicians have an opportunity to win $5,000 for study hypotheses in cardiovascular research.

The American Heart Association and PCORI (Patient-Centered Outcomes Research Institute) have announced a ‘crowdsourcing’ challenge, asking researchers and clinicians to suggest research questions that address difficult challenges identified by patients with cardiovascular diseases. Proposals should focus on questions that can be answered through comparative clinical effectiveness research with a precision medicine approach.

Submissions are due by Oct. 6. Four winners will each receive a $5,000 cash prize.

Click here to download the digital edition.

Click here to download the digital edition.

Click here to download the digital edition.

The continued use of perioperative clopidogrel is appropriate

Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.

There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR¹ and CHARISMA² have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).

But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.³

If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.⁴ This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.

That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.

No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.⁵ This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.⁶

So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.

Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.

Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Eur Heart J. 2009;30:192-201

3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s

5. J Vasc Surg. 2011;54: 779-84

6. J Vasc Surg. 2013;58: 1586-92

The continued use of perioperative clopidogrel is debatable!

There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.

However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.¹

It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.¹

To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).³

The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.

Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.⁴

It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.⁵ This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.

Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.

Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535

3. J Vasc Surg. 2016;63:1262-70

4.J Vasc Surg. 2011;54:779-84

5. Vascul Pharmacol. 2016;77:19-27

The continued use of perioperative clopidogrel is appropriate

Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.

There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR¹ and CHARISMA² have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).

But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.³

If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.⁴ This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.

That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.

No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.⁵ This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.⁶

So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.

Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.

Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Eur Heart J. 2009;30:192-201

3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s

5. J Vasc Surg. 2011;54: 779-84

6. J Vasc Surg. 2013;58: 1586-92

The continued use of perioperative clopidogrel is debatable!

There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.

However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.¹

It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.¹

To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).³

The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.

Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.⁴

It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.⁵ This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.

Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.

Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535

3. J Vasc Surg. 2016;63:1262-70

4.J Vasc Surg. 2011;54:779-84

5. Vascul Pharmacol. 2016;77:19-27

The continued use of perioperative clopidogrel is appropriate

Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.

There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR¹ and CHARISMA² have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).

But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.³

If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.⁴ This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.

That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.

No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.⁵ This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.⁶

So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.

Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.

Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Eur Heart J. 2009;30:192-201

3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s

5. J Vasc Surg. 2011;54: 779-84

6. J Vasc Surg. 2013;58: 1586-92

The continued use of perioperative clopidogrel is debatable!

There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.

However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.¹

It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.¹

To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).³

The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.

Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.⁴

It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.⁵ This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.

Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.

Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.

References

1. J Vasc Surg. 2010;52:825-33

2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535

3. J Vasc Surg. 2016;63:1262-70

4.J Vasc Surg. 2011;54:779-84

5. Vascul Pharmacol. 2016;77:19-27

The Diagnosis: Blue Toe Syndrome

The clinical manifestation suggested blue toe syndrome. A variety of causes for blue toe syndrome are known such as embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal circulating blood.¹ Among them, only emboli from atherosclerotic plaques give rise to typical cholesterol clefts on skin biopsy (Figure 1). Such atheroemboli often are an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of the cholesterol crystals, which was likely to be the case in our patient because no preceding trigger events were noted.

Other clinical features also are seen in atheroembolism. Approximately half of patients with atheroembolism develop clinical kidney disease.² Almost all iatrogenic cases have acute or subacute reduction in glomerular filtration rate of at least to 50% level, whereas the spontaneous cases present as stable chronic renal failure.³ Approximately 20% of patients with atheroembolism also have involvement of digestive organs.^4,5 Abdominal pain, diarrhea, and gastrointestinal blood loss are common features; bowel infarction and perforation occasionally occur.⁵ Pancreatitis is another common complication, and serum amylase levels are raised in approximately 50% of patients.6 Atheroemboli may reach the eyes and brain. They occasionally can cause loss of vision,⁷ as well as transient ischemic attacks, strokes, and gradual deterioration in cerebral function.³ Blood eosinophilia, which occurs in approximately 60% of patients, is an important finding.^3,8

Although there is no specific therapy for atheroembolism, the use of antiplatelet agents is considered reasonable because they are beneficial in preventing myocardial infarction in patients with atherosclerosis.⁹ In our case, the livedo reticularis cleared, as did the coldness on the affected toes after 2 weeks of sarpogrelate hydrochloride administration; however, development of necrotic change was noted (Figure 2). Necrotic change on the hallux disappeared after 2 weeks.

The Diagnosis: Blue Toe Syndrome

The clinical manifestation suggested blue toe syndrome. A variety of causes for blue toe syndrome are known such as embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal circulating blood.¹ Among them, only emboli from atherosclerotic plaques give rise to typical cholesterol clefts on skin biopsy (Figure 1). Such atheroemboli often are an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of the cholesterol crystals, which was likely to be the case in our patient because no preceding trigger events were noted.

Other clinical features also are seen in atheroembolism. Approximately half of patients with atheroembolism develop clinical kidney disease.² Almost all iatrogenic cases have acute or subacute reduction in glomerular filtration rate of at least to 50% level, whereas the spontaneous cases present as stable chronic renal failure.³ Approximately 20% of patients with atheroembolism also have involvement of digestive organs.^4,5 Abdominal pain, diarrhea, and gastrointestinal blood loss are common features; bowel infarction and perforation occasionally occur.⁵ Pancreatitis is another common complication, and serum amylase levels are raised in approximately 50% of patients.6 Atheroemboli may reach the eyes and brain. They occasionally can cause loss of vision,⁷ as well as transient ischemic attacks, strokes, and gradual deterioration in cerebral function.³ Blood eosinophilia, which occurs in approximately 60% of patients, is an important finding.^3,8

Although there is no specific therapy for atheroembolism, the use of antiplatelet agents is considered reasonable because they are beneficial in preventing myocardial infarction in patients with atherosclerosis.⁹ In our case, the livedo reticularis cleared, as did the coldness on the affected toes after 2 weeks of sarpogrelate hydrochloride administration; however, development of necrotic change was noted (Figure 2). Necrotic change on the hallux disappeared after 2 weeks.

The Diagnosis: Blue Toe Syndrome

The clinical manifestation suggested blue toe syndrome. A variety of causes for blue toe syndrome are known such as embolism, thrombosis, vasoconstrictive disorders, infectious and noninfectious inflammation, extensive venous thrombosis, and abnormal circulating blood.¹ Among them, only emboli from atherosclerotic plaques give rise to typical cholesterol clefts on skin biopsy (Figure 1). Such atheroemboli often are an iatrogenic complication, especially those caused by invasive percutaneous procedures or damage to the arterial walls from vascular surgery. However, spontaneous plaque hemorrhage or shearing forces of the circulating blood can disrupt atheromatous plaques and cause embolization of the cholesterol crystals, which was likely to be the case in our patient because no preceding trigger events were noted.

Other clinical features also are seen in atheroembolism. Approximately half of patients with atheroembolism develop clinical kidney disease.² Almost all iatrogenic cases have acute or subacute reduction in glomerular filtration rate of at least to 50% level, whereas the spontaneous cases present as stable chronic renal failure.³ Approximately 20% of patients with atheroembolism also have involvement of digestive organs.^4,5 Abdominal pain, diarrhea, and gastrointestinal blood loss are common features; bowel infarction and perforation occasionally occur.⁵ Pancreatitis is another common complication, and serum amylase levels are raised in approximately 50% of patients.6 Atheroemboli may reach the eyes and brain. They occasionally can cause loss of vision,⁷ as well as transient ischemic attacks, strokes, and gradual deterioration in cerebral function.³ Blood eosinophilia, which occurs in approximately 60% of patients, is an important finding.^3,8

Although there is no specific therapy for atheroembolism, the use of antiplatelet agents is considered reasonable because they are beneficial in preventing myocardial infarction in patients with atherosclerosis.⁹ In our case, the livedo reticularis cleared, as did the coldness on the affected toes after 2 weeks of sarpogrelate hydrochloride administration; however, development of necrotic change was noted (Figure 2). Necrotic change on the hallux disappeared after 2 weeks.