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Use of bilateral internal mammary arteries in CABG stagnates
HOUSTON – Over the past 5 years there has been no growth in bilateral internal mammary artery use among Medicare beneficiaries, and the frequency of bilateral internal mammary artery use during coronary artery bypass grafting remained low, according to a large observational analysis.
“Despite a growing evidence base supporting bilateral internal mammary artery use with regard to long-term survival and freedom from repeat revascularization, rates of bilateral internal mammary artery [BIMA] use remain low, with no evidence of growth,” Alexander Iribarne, MD, said during an interview at the annual meeting of the Society of Thoracic Surgeons. “Therefore, there is significant opportunity for adoption of bilateral internal mammary artery grafting in the United States.”
The most recent report of CABG trends in the United States published from the STS database showed that in 2009, fewer than 5% of patients who underwent CABG received a BIMA (J Thorac Cardiovasc Surg. 2012 Feb;143[2]:273-81). In an effort to characterize the adoption rate and regional variation of BIMA use in the United States, Dr. Iribarne, director of cardiac surgical research in the section of cardiac surgery at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates examined records from nearly 150 million Medicare beneficiaries from 2009-2014. “This work is unique in that we not only looked at trends in rates of usage but also how this varied by geographic location,” he said.
“I was surprised to find that despite the growing literature supporting BIMA use, there was no growth in rates of usage over the 5-year study period, with rates remaining low,” Dr. Iribarne said. “I was also surprised to see that there was significant regional variation in use that appeared to correlate, in part, with overall CABG volume, although the moderate correlation coefficient indicates that additional factors beyond CABG volume are involved.”
A key limitation of the study, he said, was that its patients were aged 65 and older. Dr. Iribarne disclosed that he receives grant funding from the American Association for Thoracic Surgery Graham Foundation and the Dartmouth SYNERGY Clinical and Translational Science Institute.
HOUSTON – Over the past 5 years there has been no growth in bilateral internal mammary artery use among Medicare beneficiaries, and the frequency of bilateral internal mammary artery use during coronary artery bypass grafting remained low, according to a large observational analysis.
“Despite a growing evidence base supporting bilateral internal mammary artery use with regard to long-term survival and freedom from repeat revascularization, rates of bilateral internal mammary artery [BIMA] use remain low, with no evidence of growth,” Alexander Iribarne, MD, said during an interview at the annual meeting of the Society of Thoracic Surgeons. “Therefore, there is significant opportunity for adoption of bilateral internal mammary artery grafting in the United States.”
The most recent report of CABG trends in the United States published from the STS database showed that in 2009, fewer than 5% of patients who underwent CABG received a BIMA (J Thorac Cardiovasc Surg. 2012 Feb;143[2]:273-81). In an effort to characterize the adoption rate and regional variation of BIMA use in the United States, Dr. Iribarne, director of cardiac surgical research in the section of cardiac surgery at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates examined records from nearly 150 million Medicare beneficiaries from 2009-2014. “This work is unique in that we not only looked at trends in rates of usage but also how this varied by geographic location,” he said.
“I was surprised to find that despite the growing literature supporting BIMA use, there was no growth in rates of usage over the 5-year study period, with rates remaining low,” Dr. Iribarne said. “I was also surprised to see that there was significant regional variation in use that appeared to correlate, in part, with overall CABG volume, although the moderate correlation coefficient indicates that additional factors beyond CABG volume are involved.”
A key limitation of the study, he said, was that its patients were aged 65 and older. Dr. Iribarne disclosed that he receives grant funding from the American Association for Thoracic Surgery Graham Foundation and the Dartmouth SYNERGY Clinical and Translational Science Institute.
HOUSTON – Over the past 5 years there has been no growth in bilateral internal mammary artery use among Medicare beneficiaries, and the frequency of bilateral internal mammary artery use during coronary artery bypass grafting remained low, according to a large observational analysis.
“Despite a growing evidence base supporting bilateral internal mammary artery use with regard to long-term survival and freedom from repeat revascularization, rates of bilateral internal mammary artery [BIMA] use remain low, with no evidence of growth,” Alexander Iribarne, MD, said during an interview at the annual meeting of the Society of Thoracic Surgeons. “Therefore, there is significant opportunity for adoption of bilateral internal mammary artery grafting in the United States.”
The most recent report of CABG trends in the United States published from the STS database showed that in 2009, fewer than 5% of patients who underwent CABG received a BIMA (J Thorac Cardiovasc Surg. 2012 Feb;143[2]:273-81). In an effort to characterize the adoption rate and regional variation of BIMA use in the United States, Dr. Iribarne, director of cardiac surgical research in the section of cardiac surgery at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., and his associates examined records from nearly 150 million Medicare beneficiaries from 2009-2014. “This work is unique in that we not only looked at trends in rates of usage but also how this varied by geographic location,” he said.
“I was surprised to find that despite the growing literature supporting BIMA use, there was no growth in rates of usage over the 5-year study period, with rates remaining low,” Dr. Iribarne said. “I was also surprised to see that there was significant regional variation in use that appeared to correlate, in part, with overall CABG volume, although the moderate correlation coefficient indicates that additional factors beyond CABG volume are involved.”
A key limitation of the study, he said, was that its patients were aged 65 and older. Dr. Iribarne disclosed that he receives grant funding from the American Association for Thoracic Surgery Graham Foundation and the Dartmouth SYNERGY Clinical and Translational Science Institute.
AT THE STS ANNUAL MEETING
Key clinical point:
Major finding: The absolute national rate of BIMA use fell from 0.216 claims per 1,000 beneficiaries in 2009 to 0.143 in 2014 (P less than .001).
Data source: An analysis of medical records from nearly 150 million Medicare beneficiaries during 2009-2014.
Disclosures: Dr. Iribarne disclosed that he receives grant funding from the American Association for Thoracic Surgery Graham Foundation and the Dartmouth SYNERGY Clinical and Translational Science Institute.
Comorbid mental illness linked to worse surgical outcomes
LAS VEGAS – A comorbid mental illness may predispose surgical patients to poor outcomes, increasing the risk of postoperative complications, a prolonged length of stay, and – in some cases – even in-hospital mortality.
The link between mental illness and physical response to surgery is not well elucidated, and is likely an extremely complicated one, Elizabeth Bailey, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.
Dr. Bailey said there is an extreme paucity of data on the relationship between mental illness and surgical outcomes. To investigate it, she examined 580,000 patient records contained in the National Inpatient Sample.
The cases spanned 2009-2011 and represented the four most common surgical procedures in the United States: cholecystectomy, appendectomy, adhesion excision/lysis, and colorectal resection.
She compared surgical outcomes among patients without a DSM-IV diagnosis and those with one of the five most common: mood disorder, anxiety, impulse control, schizophrenia, and substance abuse disorder.
The study’s primary outcomes were length of hospital stay, in-hospital mortality, and postoperative complications. Her analysis controlled for age, gender, race, admission status, operative approach, non–mental health comorbidities, insurance, and income.
Of the 580,000 in the study group 7% (39,000) had at least one of the mental health comorbidities. Mood disorder was the most common (59%), followed by substance abuse (24%), schizophrenia (13%), anxiety disorder (12%), and impulse control disorder (5%).
There were a number of significant baseline differences between those with a mental diagnosis and those without. Those with a DSM-IV diagnosis were younger (52 vs. 54 years), more often women (61% vs. 57%), and white (78% vs. 69%). They more often had additional physical comorbidities (80% vs. 68%). They were more likely to be admitted through the emergency room (74% vs. 71%), to have nonlaparoscopic surgery (60% vs 63%), to be on public insurance (53% vs. 43%), and to be in the lowest income quartile (28% vs. 25%).
Surgical outcomes were almost universally significantly worse among these patients. They were 41% more likely to experience a prolonged length of stay and 18% more likely to experience a complication. These included wound disruption, ileus, and small bowel obstruction. They faced a 24% increased risk for needing total parenteral nutrition; a 29% increased risk of abdominal pain; an 18% increased risk of percutaneous abdominal drainage; and a 15% increased risk of needing another operation in the same admission.
Dr. Bailey also broke down overall risks by DSM-IV diagnosis.
• Patients with a mood disorder were 35% more likely to have a prolonged length of stay and 13% more likely to have a surgical complication.
• Patients with an anxiety disorder were 16% more likely to have a prolonged length of stay and 10% more likely to have a complication.
• Patients with schizophrenia were 77% more likely to have a prolonged length of stay, 3% more likely to die, and 28% more likely to have a complication.
• Patients with substance abuse were 70% more likely to have a prolonged length of stay, 6% more likely to die, and 39% more likely to have a complication.
Interestingly, Dr. Bailey said, the risk of in-hospital death was 16% lower in patients with a mood disorder, 59% lower in those with an anxiety disorder, and 77% lower in those with an impulse control disorder.
She stressed that the National Inpatient Sample provides a limited look into a patient’s hospital experience. The study can’t assess how long patients were sick before they came to the hospital, their medications or medication adherence, or how well they managed their mental and physical comorbidities.
“While we lacked the means to delve into potential clinical mediators, look at unplanned readmissions, or the use of inpatient psychiatric consults, we can clearly see the association with worse surgical outcomes,” Dr. Bailey said. “Recognizing this is the first step in learning how to optimize care for this frequently marginalized population.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
LAS VEGAS – A comorbid mental illness may predispose surgical patients to poor outcomes, increasing the risk of postoperative complications, a prolonged length of stay, and – in some cases – even in-hospital mortality.
The link between mental illness and physical response to surgery is not well elucidated, and is likely an extremely complicated one, Elizabeth Bailey, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.
Dr. Bailey said there is an extreme paucity of data on the relationship between mental illness and surgical outcomes. To investigate it, she examined 580,000 patient records contained in the National Inpatient Sample.
The cases spanned 2009-2011 and represented the four most common surgical procedures in the United States: cholecystectomy, appendectomy, adhesion excision/lysis, and colorectal resection.
She compared surgical outcomes among patients without a DSM-IV diagnosis and those with one of the five most common: mood disorder, anxiety, impulse control, schizophrenia, and substance abuse disorder.
The study’s primary outcomes were length of hospital stay, in-hospital mortality, and postoperative complications. Her analysis controlled for age, gender, race, admission status, operative approach, non–mental health comorbidities, insurance, and income.
Of the 580,000 in the study group 7% (39,000) had at least one of the mental health comorbidities. Mood disorder was the most common (59%), followed by substance abuse (24%), schizophrenia (13%), anxiety disorder (12%), and impulse control disorder (5%).
There were a number of significant baseline differences between those with a mental diagnosis and those without. Those with a DSM-IV diagnosis were younger (52 vs. 54 years), more often women (61% vs. 57%), and white (78% vs. 69%). They more often had additional physical comorbidities (80% vs. 68%). They were more likely to be admitted through the emergency room (74% vs. 71%), to have nonlaparoscopic surgery (60% vs 63%), to be on public insurance (53% vs. 43%), and to be in the lowest income quartile (28% vs. 25%).
Surgical outcomes were almost universally significantly worse among these patients. They were 41% more likely to experience a prolonged length of stay and 18% more likely to experience a complication. These included wound disruption, ileus, and small bowel obstruction. They faced a 24% increased risk for needing total parenteral nutrition; a 29% increased risk of abdominal pain; an 18% increased risk of percutaneous abdominal drainage; and a 15% increased risk of needing another operation in the same admission.
Dr. Bailey also broke down overall risks by DSM-IV diagnosis.
• Patients with a mood disorder were 35% more likely to have a prolonged length of stay and 13% more likely to have a surgical complication.
• Patients with an anxiety disorder were 16% more likely to have a prolonged length of stay and 10% more likely to have a complication.
• Patients with schizophrenia were 77% more likely to have a prolonged length of stay, 3% more likely to die, and 28% more likely to have a complication.
• Patients with substance abuse were 70% more likely to have a prolonged length of stay, 6% more likely to die, and 39% more likely to have a complication.
Interestingly, Dr. Bailey said, the risk of in-hospital death was 16% lower in patients with a mood disorder, 59% lower in those with an anxiety disorder, and 77% lower in those with an impulse control disorder.
She stressed that the National Inpatient Sample provides a limited look into a patient’s hospital experience. The study can’t assess how long patients were sick before they came to the hospital, their medications or medication adherence, or how well they managed their mental and physical comorbidities.
“While we lacked the means to delve into potential clinical mediators, look at unplanned readmissions, or the use of inpatient psychiatric consults, we can clearly see the association with worse surgical outcomes,” Dr. Bailey said. “Recognizing this is the first step in learning how to optimize care for this frequently marginalized population.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
LAS VEGAS – A comorbid mental illness may predispose surgical patients to poor outcomes, increasing the risk of postoperative complications, a prolonged length of stay, and – in some cases – even in-hospital mortality.
The link between mental illness and physical response to surgery is not well elucidated, and is likely an extremely complicated one, Elizabeth Bailey, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.
Dr. Bailey said there is an extreme paucity of data on the relationship between mental illness and surgical outcomes. To investigate it, she examined 580,000 patient records contained in the National Inpatient Sample.
The cases spanned 2009-2011 and represented the four most common surgical procedures in the United States: cholecystectomy, appendectomy, adhesion excision/lysis, and colorectal resection.
She compared surgical outcomes among patients without a DSM-IV diagnosis and those with one of the five most common: mood disorder, anxiety, impulse control, schizophrenia, and substance abuse disorder.
The study’s primary outcomes were length of hospital stay, in-hospital mortality, and postoperative complications. Her analysis controlled for age, gender, race, admission status, operative approach, non–mental health comorbidities, insurance, and income.
Of the 580,000 in the study group 7% (39,000) had at least one of the mental health comorbidities. Mood disorder was the most common (59%), followed by substance abuse (24%), schizophrenia (13%), anxiety disorder (12%), and impulse control disorder (5%).
There were a number of significant baseline differences between those with a mental diagnosis and those without. Those with a DSM-IV diagnosis were younger (52 vs. 54 years), more often women (61% vs. 57%), and white (78% vs. 69%). They more often had additional physical comorbidities (80% vs. 68%). They were more likely to be admitted through the emergency room (74% vs. 71%), to have nonlaparoscopic surgery (60% vs 63%), to be on public insurance (53% vs. 43%), and to be in the lowest income quartile (28% vs. 25%).
Surgical outcomes were almost universally significantly worse among these patients. They were 41% more likely to experience a prolonged length of stay and 18% more likely to experience a complication. These included wound disruption, ileus, and small bowel obstruction. They faced a 24% increased risk for needing total parenteral nutrition; a 29% increased risk of abdominal pain; an 18% increased risk of percutaneous abdominal drainage; and a 15% increased risk of needing another operation in the same admission.
Dr. Bailey also broke down overall risks by DSM-IV diagnosis.
• Patients with a mood disorder were 35% more likely to have a prolonged length of stay and 13% more likely to have a surgical complication.
• Patients with an anxiety disorder were 16% more likely to have a prolonged length of stay and 10% more likely to have a complication.
• Patients with schizophrenia were 77% more likely to have a prolonged length of stay, 3% more likely to die, and 28% more likely to have a complication.
• Patients with substance abuse were 70% more likely to have a prolonged length of stay, 6% more likely to die, and 39% more likely to have a complication.
Interestingly, Dr. Bailey said, the risk of in-hospital death was 16% lower in patients with a mood disorder, 59% lower in those with an anxiety disorder, and 77% lower in those with an impulse control disorder.
She stressed that the National Inpatient Sample provides a limited look into a patient’s hospital experience. The study can’t assess how long patients were sick before they came to the hospital, their medications or medication adherence, or how well they managed their mental and physical comorbidities.
“While we lacked the means to delve into potential clinical mediators, look at unplanned readmissions, or the use of inpatient psychiatric consults, we can clearly see the association with worse surgical outcomes,” Dr. Bailey said. “Recognizing this is the first step in learning how to optimize care for this frequently marginalized population.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
AT THE ACADEMIC SURGICAL CONGRESS
Key clinical point:
Major finding: They were 41% more likely to experience a prolonged length of stay and 18% more likely to experience a complication.
Data source: The database review comprised 580,000 patients.
Disclosures: Dr. Bailey had no financial disclosures.
New AJCC guidance brings melanoma staging changes
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.
The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.
The eighth edition breaks new ground, moving beyond TNM (Tumor, Node, Metastasis) anatomic staging to incorporate new evidence-based prognostic factors.
“There are some subtle differences here to be aware of. It can be a little bit tricky at first glance. You should become familiar with this,” advised Dr. Marchetti, a dermatologist at Memorial Sloan-Kettering Cancer Center in New York.
In addition to highlighting the changes in melanoma staging included in the new AJCC manual, he outlined key recommendations – some of them controversial – on the use of sentinel lymph node biopsy (SLNB) in melanoma patients incorporated in the 2017 National Comprehensive Cancer Network (NCCN) guidelines.
The biggest change for the dermatology community contained in the new edition of the AJCC staging manual is that the T1 classification of melanoma has changed. In the seventh edition, a melanoma was categorized as T1 if less than or equal to 1.0 mm thickness. The cancer was T1a if nonulcerated and had a mitosis rate of less than 1/mm2 and T1b if ulcerated or had at least 1 mitosis/mm2.
The eighth edition makes an evidence-based subcategorization of T1 based upon thickness in light of the prognostic implications of this distinction. A melanoma is defined as T1a if nonulcerated and less than 0.8 mm in thickness, and T1b if it is 0.8-1.0 mm thick or less than 0.8 mm with ulceration.
Of note, tumor mitotic rate has been dropped as a staging criterion for T1 tumors.
What this means is, for example, in 2017, a patient with a 0.9-mm nonulcerated melanoma with 1 mitosis/mm2 and a negative sentinel lymph node biopsy with wide local excision is T1bN0M0, pathologic Stage IB. Under the eighth edition of AJCC, the same patient is T1bN0M0, pathologic Stage IA, because that mitosis rate isn’t a factor.
Today, a patient with a 0.5-mm melanoma with 1 mitosis/mm2 with wide local excision is T1bN0M0, Pathologic Stage IB. Under the new system, the same tumor is downstaged to Pathologic Stage IA, Dr. Marchetti explained.
In the eighth edition, tumor thickness measurements are recorded with rounding to the nearest 0.1 mm, not to the nearest 0.01 mm as before. This change was prompted by the inherent lack of precision in measuring melanomas, especially thicker ones.
The T category definitions of primary tumors have been clarified in the eighth edition. A tumor should be classified as T0 only if there is no evidence of a primary tumor. T is utilized for melanoma in situ. TX is employed when the primary tumor thickness can’t be determined, as for example when the biopsy specimen was obtained through curettage.
The N categorization of regional lymph node status has become much more complicated in the eighth edition, the dermatologist cautioned. Plus, the terminology for nodal disease has changed. The term micrometastasis has been replaced by “clinically occult disease” as detected by SLNB. Macrometastasis has been supplanted by “clinically detected disease.” And while in-transit or satellite node metastasis or microsatellite metastasis with satellite nodes was formerly listed simply as N3, in the new system there are subcategories for N3 based upon the number of metastatic nodes involved. For example, in the eighth edition, a melanoma is pathologic Stage N3a if there are four or more clinically occult regional lymph nodes and no in-transit, satellite, or matted nodes. Pathologic Stage N3b is shorthand for four or more tumor-involved regional lymph nodes, at least one of which was clinically detected, or any number of matted lymph nodes, with no in-transit or satellite nodal involvement. Stage N3c is reserved for melanomas with two or more clinically occult or clinically detected regional lymph nodes and/or any number of matted nodes, plus the presence of in-transit or satellite nodal metastasis.
As a result of the changes in the N classification, there are now four pathologic Stage III groups rather than three. Stages IIIA-C have been joined by pathologic Stage IIID, reserved for patients who are T4b, N3a, b, or c, and M0.
The M categorization of distant metastatic disease status has also become more elaborate. In the AJCC seventh edition, if serum lactate dehydrogenase (LDH) is elevated and a patient has any distant metastatic disease, that’s automatically category M1c. Not any longer, though.
Under the eighth edition, if a patient has distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes and the LDH is unspecified, the categorization is M1a. If serum LDH is not elevated, it’s M1a(0). If elevated, then M1a(1).
Similarly, for distant metastasis to the lung, the range of possibilities based upon LDH is M1b, M1b(0), and M1b(1). For distant metastasis to non-CNS visceral sites, the possibilities are M1c, M1c(0), and M1c(1).
M1d is a new classification, a clear departure from the seventh edition. It applies to patients with distant metastasis to the CNS. The classification is M1d if LDH isn’t recorded, M1d(0) if LDH isn’t elevated, and M1d(1) if it is.
Turning to the updated 2017 NCCN guidelines Version 1.2017 on the role of SLNB in melanoma, Dr. Marchetti noted that the procedure is not recommended in patients with melanoma in situ or Stage IA or IB disease 0.75 mm or less in thickness, regardless of features. Neither are routine imaging or lab tests. That’s because the pretest probability of a positive SLNB is so low, at around 3%.
For Clinicopathologic Stage IA disease, 0.76-1.0 mm in thickness with no ulceration and a mitotic rate of less than 1 per mm2, the guidelines recommend that physicians “discuss and consider” SLNB, which the available evidence suggests has roughly a 7% pretest probability of a positive result.
For Stage IB disease, 0.76-1.0 mm in thickness with ulceration or a mitotic rate of at least 1 per mm2, as well as for Stage IB or Stage II disease greater than 1.0 mm in thickness, with any feature, the language of the recommendation shifts to “discuss and offer” rather than “discuss and consider” SLNB, since various studies have reported pretest probabilities of a positive result as high as 35%.
“The rationale here for performing sentinel lymph node biopsy is primarily to acquire more staging information. Is it a perfect test? Absolutely not. But it’s the current standard of care in terms of providing additional information for staging,” according to Dr. Marchetti.
If the SLNB generates a positive result, by definition the patient now has Stage III melanoma. The NCCN guidelines recommend consideration of imaging to establish a baseline, and state further that the primary treatment is to discuss and offer complete lymph node dissection in order to control the regional nodal basin and because of a possible favorable impact on overall survival. But the question of a survival benefit has been controversial for many years, and it’s unlikely to be resolved soon, Dr. Marchetti predicted.
The final report from the National Cancer Institute–sponsored Multicenter Selective Lymphadenectomy Trial–1 (MSLT-1) concluded that patients with primary cutaneous melanomas 1.2 mm or more in thickness who were randomized to undergo SLNB and, if positive, immediate complete lymphadenectomy, fared significantly better in terms of 10-year disease-free survival, compared with those assigned to observation and lymphadenectomy in the event of nodal relapse (N Engl J Med. 2014 Feb 13;370[7]:599-609).
This conclusion has generated numerous letters to the editor from melanoma experts who took issue with the analysis and conclusion. To try to put the MSLT-1 results in perspective, Dr. Marchetti applied the results to a hypothetical cohort of 100 patients with intermediate-thickness melanomas of 1.2-3.5 mm undergoing SLNB.
Eighty of these patients would be true SLNB-negative for regional nodal disease. Five others would have a false-negative SLNB and would later develop clinically detectable nodal disease. Fifteen patients with a positive SLNB would undergo prompt complete lymph node dissection, of whom 12 or 13 would derive no mortality benefit at 10 years, assuming the MSLT-1 investigators are correct in their analysis.
“Two or three patients with a positive SLNB will derive mortality benefit at 10 years, but we have no way to identify who those people are from the original 100,” he said.
Since the MSLT-1 report, a phase III German multicenter randomized trial of 241 melanoma patients with a positive screening SLNB has reported results. The participants assigned to complete lymph node dissection didn’t differ in terms of 3-year overall survival, distant metastasis-free survival, or recurrence-free survival, compared with those assigned to observation and lymphadenectomy if nodal disease occurred (Lancet Oncol. 2016 Jun;17[6]:757-67). However, as the investigators noted, the study, known as DeCOG-SLT, was underpowered, and Dr. Marchetti’s view is that it can’t be considered definitive.
“Ultimately I don’t think we’ll have a definitive answer to this question until the final results of the MSLT-II trial in the fall of 2022,” he said.
The MSLT-II trial has the same design as DeCOG-SLT.
Dr. Marchetti reported having no financial conflicts of interest regarding his presentation.
SDEF and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM THE SDEF HAWAII DERMATOLOGY SEMINAR
Esophageal retractor found handy tool in AF ablation
ORLANDO – A relatively simple mechanical tool to move the esophagus away from the energy delivered during ablation of atrial fibrillation (AF) does what it is supposed to do, according to data from a multicenter observational study presented at the AF Symposium 2017.
When esophageal temperature during the ablation procedure was monitored in 101 consecutive cases, no recording exceeded 38° C, according to Valay Parikh, MD, a clinical cardiac electrophysiology fellow working under Dhanunjaya Lakkireddy, MD, at the Kansas University Medical Center, Kansas City.
The tool is a stylet constructed from a nickel-titanium (nitinol) alloy. Malleable at room temperature, the stylet is inserted into an 18 Fr orogastric (OG) tube. Firmer at body temperature, the stylet within the OG tube is maneuvered to displace the esophagus away from the adjacent left atrium when radiofrequency ablation (RFA) is being administered.
The tool, marketed under the brand name EsoSure, was first made available almost 2 years ago, but the recently completed multicenter observational study was conducted to provide a more systematic evaluation of its safety and efficacy in routine use. In this study, 101 consecutive patients scheduled for RFA for AF had their esophagus displaced by the stylet during the procedure. The temperature of the esophagus as well as any adverse events involving the upper gastrointestinal tract were evaluated during the procedure. Patients were then followed for at least 6 months.
“The principal finding of our study is that mechanical displacement of the esophagus with the help of the EsoSure device is safe and provides sufficient room to deliver the intended energy at the site of ablation without any rise in temperature over 38° C,” Dr. Parikh reported.
The mean age of the 101 patients who participated in this study was 65 years. About half were female. The mean body mass index (BMI) was 32 kg/m2. The mean CHA2DS2-VASc score was 2.4. Barium x-rays were used to confirm esophageal displacement.
After the procedure, patients were discharged on a proton pump inhibitor and sucralfate, which inhibits pepsin activity and protects against ulceration. Follow-up endoscopy was performed only when medically indicated, but all patients were evaluated over the course of follow-up for odynophagia, dysphagia, hematemesis, dyspepsia, and other GI symptoms.
Pulmonary vein isolation (PVI) was achieved successfully in all cases. Although there was a rapid temperature rise at the site of ablation over the course of RFA, the esophagus was adequately displaced from the source of energy, as confirmed with the absence of significant temperature rises in this tissue. The mean esophageal displacement was 2.53 cm.
The only complication in this series, occurring in 7% of patients, was dysphagia. All cases of dysphagia developed immediately or soon after the procedure. All were mild, and all resolved within several days. There were no late GI complications observed, although Dr. Parikh acknowledged that no follow-up endoscopy was performed to rule out any esophageal injury.
In contrast, without the deviation permitted by the esophageal retractor, the rapid rise in temperature “could have precluded PVI,” Dr. Parikh maintained. He said that the retractor permitted the esophagus to be cleared from potential injury, as indicated by the lack of a temperature rise in esophageal tissue, in 100% of the cases. He noted that the tool is now in routine use at his center.
According to Dr. Lakkireddy, this tool is already in routine use at several centers across the country. The goal of this study was to provide an objective documentation of the ability of the device to enable successful posterior wall isolation during PVI without esophageal injury.
“It helped us get to the endpoint without a problem 100% of the time,” Dr. Lakkireddy reported.
Dr. Parikh has no industry relationships relevant to this study.
ORLANDO – A relatively simple mechanical tool to move the esophagus away from the energy delivered during ablation of atrial fibrillation (AF) does what it is supposed to do, according to data from a multicenter observational study presented at the AF Symposium 2017.
When esophageal temperature during the ablation procedure was monitored in 101 consecutive cases, no recording exceeded 38° C, according to Valay Parikh, MD, a clinical cardiac electrophysiology fellow working under Dhanunjaya Lakkireddy, MD, at the Kansas University Medical Center, Kansas City.
The tool is a stylet constructed from a nickel-titanium (nitinol) alloy. Malleable at room temperature, the stylet is inserted into an 18 Fr orogastric (OG) tube. Firmer at body temperature, the stylet within the OG tube is maneuvered to displace the esophagus away from the adjacent left atrium when radiofrequency ablation (RFA) is being administered.
The tool, marketed under the brand name EsoSure, was first made available almost 2 years ago, but the recently completed multicenter observational study was conducted to provide a more systematic evaluation of its safety and efficacy in routine use. In this study, 101 consecutive patients scheduled for RFA for AF had their esophagus displaced by the stylet during the procedure. The temperature of the esophagus as well as any adverse events involving the upper gastrointestinal tract were evaluated during the procedure. Patients were then followed for at least 6 months.
“The principal finding of our study is that mechanical displacement of the esophagus with the help of the EsoSure device is safe and provides sufficient room to deliver the intended energy at the site of ablation without any rise in temperature over 38° C,” Dr. Parikh reported.
The mean age of the 101 patients who participated in this study was 65 years. About half were female. The mean body mass index (BMI) was 32 kg/m2. The mean CHA2DS2-VASc score was 2.4. Barium x-rays were used to confirm esophageal displacement.
After the procedure, patients were discharged on a proton pump inhibitor and sucralfate, which inhibits pepsin activity and protects against ulceration. Follow-up endoscopy was performed only when medically indicated, but all patients were evaluated over the course of follow-up for odynophagia, dysphagia, hematemesis, dyspepsia, and other GI symptoms.
Pulmonary vein isolation (PVI) was achieved successfully in all cases. Although there was a rapid temperature rise at the site of ablation over the course of RFA, the esophagus was adequately displaced from the source of energy, as confirmed with the absence of significant temperature rises in this tissue. The mean esophageal displacement was 2.53 cm.
The only complication in this series, occurring in 7% of patients, was dysphagia. All cases of dysphagia developed immediately or soon after the procedure. All were mild, and all resolved within several days. There were no late GI complications observed, although Dr. Parikh acknowledged that no follow-up endoscopy was performed to rule out any esophageal injury.
In contrast, without the deviation permitted by the esophageal retractor, the rapid rise in temperature “could have precluded PVI,” Dr. Parikh maintained. He said that the retractor permitted the esophagus to be cleared from potential injury, as indicated by the lack of a temperature rise in esophageal tissue, in 100% of the cases. He noted that the tool is now in routine use at his center.
According to Dr. Lakkireddy, this tool is already in routine use at several centers across the country. The goal of this study was to provide an objective documentation of the ability of the device to enable successful posterior wall isolation during PVI without esophageal injury.
“It helped us get to the endpoint without a problem 100% of the time,” Dr. Lakkireddy reported.
Dr. Parikh has no industry relationships relevant to this study.
ORLANDO – A relatively simple mechanical tool to move the esophagus away from the energy delivered during ablation of atrial fibrillation (AF) does what it is supposed to do, according to data from a multicenter observational study presented at the AF Symposium 2017.
When esophageal temperature during the ablation procedure was monitored in 101 consecutive cases, no recording exceeded 38° C, according to Valay Parikh, MD, a clinical cardiac electrophysiology fellow working under Dhanunjaya Lakkireddy, MD, at the Kansas University Medical Center, Kansas City.
The tool is a stylet constructed from a nickel-titanium (nitinol) alloy. Malleable at room temperature, the stylet is inserted into an 18 Fr orogastric (OG) tube. Firmer at body temperature, the stylet within the OG tube is maneuvered to displace the esophagus away from the adjacent left atrium when radiofrequency ablation (RFA) is being administered.
The tool, marketed under the brand name EsoSure, was first made available almost 2 years ago, but the recently completed multicenter observational study was conducted to provide a more systematic evaluation of its safety and efficacy in routine use. In this study, 101 consecutive patients scheduled for RFA for AF had their esophagus displaced by the stylet during the procedure. The temperature of the esophagus as well as any adverse events involving the upper gastrointestinal tract were evaluated during the procedure. Patients were then followed for at least 6 months.
“The principal finding of our study is that mechanical displacement of the esophagus with the help of the EsoSure device is safe and provides sufficient room to deliver the intended energy at the site of ablation without any rise in temperature over 38° C,” Dr. Parikh reported.
The mean age of the 101 patients who participated in this study was 65 years. About half were female. The mean body mass index (BMI) was 32 kg/m2. The mean CHA2DS2-VASc score was 2.4. Barium x-rays were used to confirm esophageal displacement.
After the procedure, patients were discharged on a proton pump inhibitor and sucralfate, which inhibits pepsin activity and protects against ulceration. Follow-up endoscopy was performed only when medically indicated, but all patients were evaluated over the course of follow-up for odynophagia, dysphagia, hematemesis, dyspepsia, and other GI symptoms.
Pulmonary vein isolation (PVI) was achieved successfully in all cases. Although there was a rapid temperature rise at the site of ablation over the course of RFA, the esophagus was adequately displaced from the source of energy, as confirmed with the absence of significant temperature rises in this tissue. The mean esophageal displacement was 2.53 cm.
The only complication in this series, occurring in 7% of patients, was dysphagia. All cases of dysphagia developed immediately or soon after the procedure. All were mild, and all resolved within several days. There were no late GI complications observed, although Dr. Parikh acknowledged that no follow-up endoscopy was performed to rule out any esophageal injury.
In contrast, without the deviation permitted by the esophageal retractor, the rapid rise in temperature “could have precluded PVI,” Dr. Parikh maintained. He said that the retractor permitted the esophagus to be cleared from potential injury, as indicated by the lack of a temperature rise in esophageal tissue, in 100% of the cases. He noted that the tool is now in routine use at his center.
According to Dr. Lakkireddy, this tool is already in routine use at several centers across the country. The goal of this study was to provide an objective documentation of the ability of the device to enable successful posterior wall isolation during PVI without esophageal injury.
“It helped us get to the endpoint without a problem 100% of the time,” Dr. Lakkireddy reported.
Dr. Parikh has no industry relationships relevant to this study.
AT THE INTERNATIONAL AF SYMPOSIUM
Key clinical point: The efficacy of a tool to move the esophagus out of the way when performing ablation for atrial fibrillation is supported by a multicenter study.
Major finding: In 101 consecutive cases at four centers, all ablations were completed successfully with no esophageal temperature rise.
Data source: Prospective observational study.
Disclosures: Dr. Parikh has no industry relationships relevant to this study.
VIDEO: Dual antibiotic prophylaxis cuts cesarean SSIs
LAS VEGAS – Two days of prophylaxis with two oral antibiotics cut the surgical site infection rate by more than half in a randomized trial with more than 400 obese women who had cesarean deliveries.
The protective effect from combined treatment with cephalexin and metronidazole was especially powerful in the most at-risk patients, women with ruptured membranes before cesarean surgery. In this subgroup prophylaxis with the two antibiotics for 2 days cut surgical site infections (SSIs) during the 30 days after surgery, from a rate of 33% in control women who received placebo to a 10% rate, a 77% relative risk reduction that was statistically significant, Carri R. Warshak, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal and Fetal Medicine.
“I am very excited that we found a way to help the kinds of women in the study, very-high-risk women, with an effective way to reduce their risk of infection,” Dr. Warshak of the University of Cincinnati said in a video interview. The obese women enrolled in the study, especially those with ruptured membranes, “have a very high risk of morbidity, so it’s very exciting that we found a way to help prevent” SSIs.
“Our study is the first to target postpartum interventions to reduce SSIs specifically in this high-risk population” of obese mothers, said Amy M. Valent, DO, a maternal fetal medicine clinician at Oregon Health & Science University in Portland, who ran the trial with Dr. Warshak.
The trial randomized women with a body mass index of at least 30 kg/m2 who underwent a planned or unplanned cesarean delivery at the University of Cincinnati during 2010-2015. Following standard management during cesarean delivery, the women received either 500 mg oral cephalexin and 500 mg oral metronidazole or placebo every 8 hours for 48 hours following delivery. The primary outcome was the incidence of SSIs, and randomization was stratified so that similar numbers of women with ruptured membranes got into each treatment arm. The enrolled women averaged 28 years of age, and average BMI was about 40 kg/m2. Nearly a third of the women had ruptured membranes at the time of surgery, more than a quarter of the enrolled women used tobacco, and more than a fifth had preeclampsia.
Additional analyses reported at the meeting by Dr. Valent showed that other risk factors that significantly boosted the rate of SSIs were labor prior to delivery, use of internal monitoring, and operative time of more than 90 minutes. Antibiotic prophylaxis was able to significantly reduce SSI rates in women with any of these additional risk factors, compared with placebo. A cost effectiveness analysis she ran estimated that if the antibiotic prophylaxis tested in the study were used on the roughly 460,000 obese U.S. women having cesarean deliveries annually, it would be cost saving as long as the antibiotic regimen cost no more than $357 a person. Factoring in the SSIs and long-term morbidity that prophylaxis would prevent, and the quality-adjusted life-years it would add, showed that prophylaxis would be cost-effective up to a cost of $33,557 per woman.
The prophylaxis carries a “relatively low cost and is easy to use,” Dr. Valent said.
Safety of the antibiotic combination was a question raised by Laura E. Riley, MD, director of ob.gyn. infectious disease and labor and delivery at Massachusetts General Hospital in Boston. “My biggest concern is 48 hours of these antibiotics,” and whether prophylaxis could be achieved with fewer doses, she said in an interview. “I’d want to minimize the dosage, and also try other, nondrug approaches to minimizing SSI risk in obese women.”
“I wouldn’t say that universally, every obstetrical program should do this, but clinicians should look at the comorbidities their mothers have and their SSI rates. There are populations out there at lower risk, but there are also populations like ours, with a SSI rate of 10%-20%,” Dr. Warshak said.
She also acknowledged that even her own obstetrical group in Cincinnati needs to now reach a consensus on an appropriate strategy for expanded cesarean-delivery prophylaxis. That’s because a 2016 report from a large, randomized trial documented another successful strategy for limiting infections following cesarean delivery: a preoperative intravenous dose of azithromycin as a supplement to standard cefazolin. The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial, done in women with any BMI but specifically nonelective cesarean deliveries, showed a significant reduction in the combined rate of SSIs, endometritis, or any other infection during 6 weeks of follow-up among women who received azithromycin on top of standard prophylaxis (N Engl J Med. 2016 Sept 29;375[13]:1231-41).
“The bottom line is that, a couple of grams of cefazolin [administered before the incision] isn’t enough, especially for women with risk factors for infection. We see infection rates of more than 10% because cefazolin alone is simply inadequate. The results from both our study and the 2016 study show we can do better to reduce morbidity,” said Dr. Warshak.
“In high-risk women, such as those who are obese, we probably need to expand the spectrum and duration of prophylaxis,” agreed Dr. Main. “Obesity is one high-risk group, but there are others.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
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On Twitter @mitchelzoler
LAS VEGAS – Two days of prophylaxis with two oral antibiotics cut the surgical site infection rate by more than half in a randomized trial with more than 400 obese women who had cesarean deliveries.
The protective effect from combined treatment with cephalexin and metronidazole was especially powerful in the most at-risk patients, women with ruptured membranes before cesarean surgery. In this subgroup prophylaxis with the two antibiotics for 2 days cut surgical site infections (SSIs) during the 30 days after surgery, from a rate of 33% in control women who received placebo to a 10% rate, a 77% relative risk reduction that was statistically significant, Carri R. Warshak, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal and Fetal Medicine.
“I am very excited that we found a way to help the kinds of women in the study, very-high-risk women, with an effective way to reduce their risk of infection,” Dr. Warshak of the University of Cincinnati said in a video interview. The obese women enrolled in the study, especially those with ruptured membranes, “have a very high risk of morbidity, so it’s very exciting that we found a way to help prevent” SSIs.
“Our study is the first to target postpartum interventions to reduce SSIs specifically in this high-risk population” of obese mothers, said Amy M. Valent, DO, a maternal fetal medicine clinician at Oregon Health & Science University in Portland, who ran the trial with Dr. Warshak.
The trial randomized women with a body mass index of at least 30 kg/m2 who underwent a planned or unplanned cesarean delivery at the University of Cincinnati during 2010-2015. Following standard management during cesarean delivery, the women received either 500 mg oral cephalexin and 500 mg oral metronidazole or placebo every 8 hours for 48 hours following delivery. The primary outcome was the incidence of SSIs, and randomization was stratified so that similar numbers of women with ruptured membranes got into each treatment arm. The enrolled women averaged 28 years of age, and average BMI was about 40 kg/m2. Nearly a third of the women had ruptured membranes at the time of surgery, more than a quarter of the enrolled women used tobacco, and more than a fifth had preeclampsia.
Additional analyses reported at the meeting by Dr. Valent showed that other risk factors that significantly boosted the rate of SSIs were labor prior to delivery, use of internal monitoring, and operative time of more than 90 minutes. Antibiotic prophylaxis was able to significantly reduce SSI rates in women with any of these additional risk factors, compared with placebo. A cost effectiveness analysis she ran estimated that if the antibiotic prophylaxis tested in the study were used on the roughly 460,000 obese U.S. women having cesarean deliveries annually, it would be cost saving as long as the antibiotic regimen cost no more than $357 a person. Factoring in the SSIs and long-term morbidity that prophylaxis would prevent, and the quality-adjusted life-years it would add, showed that prophylaxis would be cost-effective up to a cost of $33,557 per woman.
The prophylaxis carries a “relatively low cost and is easy to use,” Dr. Valent said.
Safety of the antibiotic combination was a question raised by Laura E. Riley, MD, director of ob.gyn. infectious disease and labor and delivery at Massachusetts General Hospital in Boston. “My biggest concern is 48 hours of these antibiotics,” and whether prophylaxis could be achieved with fewer doses, she said in an interview. “I’d want to minimize the dosage, and also try other, nondrug approaches to minimizing SSI risk in obese women.”
“I wouldn’t say that universally, every obstetrical program should do this, but clinicians should look at the comorbidities their mothers have and their SSI rates. There are populations out there at lower risk, but there are also populations like ours, with a SSI rate of 10%-20%,” Dr. Warshak said.
She also acknowledged that even her own obstetrical group in Cincinnati needs to now reach a consensus on an appropriate strategy for expanded cesarean-delivery prophylaxis. That’s because a 2016 report from a large, randomized trial documented another successful strategy for limiting infections following cesarean delivery: a preoperative intravenous dose of azithromycin as a supplement to standard cefazolin. The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial, done in women with any BMI but specifically nonelective cesarean deliveries, showed a significant reduction in the combined rate of SSIs, endometritis, or any other infection during 6 weeks of follow-up among women who received azithromycin on top of standard prophylaxis (N Engl J Med. 2016 Sept 29;375[13]:1231-41).
“The bottom line is that, a couple of grams of cefazolin [administered before the incision] isn’t enough, especially for women with risk factors for infection. We see infection rates of more than 10% because cefazolin alone is simply inadequate. The results from both our study and the 2016 study show we can do better to reduce morbidity,” said Dr. Warshak.
“In high-risk women, such as those who are obese, we probably need to expand the spectrum and duration of prophylaxis,” agreed Dr. Main. “Obesity is one high-risk group, but there are others.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
LAS VEGAS – Two days of prophylaxis with two oral antibiotics cut the surgical site infection rate by more than half in a randomized trial with more than 400 obese women who had cesarean deliveries.
The protective effect from combined treatment with cephalexin and metronidazole was especially powerful in the most at-risk patients, women with ruptured membranes before cesarean surgery. In this subgroup prophylaxis with the two antibiotics for 2 days cut surgical site infections (SSIs) during the 30 days after surgery, from a rate of 33% in control women who received placebo to a 10% rate, a 77% relative risk reduction that was statistically significant, Carri R. Warshak, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal and Fetal Medicine.
“I am very excited that we found a way to help the kinds of women in the study, very-high-risk women, with an effective way to reduce their risk of infection,” Dr. Warshak of the University of Cincinnati said in a video interview. The obese women enrolled in the study, especially those with ruptured membranes, “have a very high risk of morbidity, so it’s very exciting that we found a way to help prevent” SSIs.
“Our study is the first to target postpartum interventions to reduce SSIs specifically in this high-risk population” of obese mothers, said Amy M. Valent, DO, a maternal fetal medicine clinician at Oregon Health & Science University in Portland, who ran the trial with Dr. Warshak.
The trial randomized women with a body mass index of at least 30 kg/m2 who underwent a planned or unplanned cesarean delivery at the University of Cincinnati during 2010-2015. Following standard management during cesarean delivery, the women received either 500 mg oral cephalexin and 500 mg oral metronidazole or placebo every 8 hours for 48 hours following delivery. The primary outcome was the incidence of SSIs, and randomization was stratified so that similar numbers of women with ruptured membranes got into each treatment arm. The enrolled women averaged 28 years of age, and average BMI was about 40 kg/m2. Nearly a third of the women had ruptured membranes at the time of surgery, more than a quarter of the enrolled women used tobacco, and more than a fifth had preeclampsia.
Additional analyses reported at the meeting by Dr. Valent showed that other risk factors that significantly boosted the rate of SSIs were labor prior to delivery, use of internal monitoring, and operative time of more than 90 minutes. Antibiotic prophylaxis was able to significantly reduce SSI rates in women with any of these additional risk factors, compared with placebo. A cost effectiveness analysis she ran estimated that if the antibiotic prophylaxis tested in the study were used on the roughly 460,000 obese U.S. women having cesarean deliveries annually, it would be cost saving as long as the antibiotic regimen cost no more than $357 a person. Factoring in the SSIs and long-term morbidity that prophylaxis would prevent, and the quality-adjusted life-years it would add, showed that prophylaxis would be cost-effective up to a cost of $33,557 per woman.
The prophylaxis carries a “relatively low cost and is easy to use,” Dr. Valent said.
Safety of the antibiotic combination was a question raised by Laura E. Riley, MD, director of ob.gyn. infectious disease and labor and delivery at Massachusetts General Hospital in Boston. “My biggest concern is 48 hours of these antibiotics,” and whether prophylaxis could be achieved with fewer doses, she said in an interview. “I’d want to minimize the dosage, and also try other, nondrug approaches to minimizing SSI risk in obese women.”
“I wouldn’t say that universally, every obstetrical program should do this, but clinicians should look at the comorbidities their mothers have and their SSI rates. There are populations out there at lower risk, but there are also populations like ours, with a SSI rate of 10%-20%,” Dr. Warshak said.
She also acknowledged that even her own obstetrical group in Cincinnati needs to now reach a consensus on an appropriate strategy for expanded cesarean-delivery prophylaxis. That’s because a 2016 report from a large, randomized trial documented another successful strategy for limiting infections following cesarean delivery: a preoperative intravenous dose of azithromycin as a supplement to standard cefazolin. The Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial, done in women with any BMI but specifically nonelective cesarean deliveries, showed a significant reduction in the combined rate of SSIs, endometritis, or any other infection during 6 weeks of follow-up among women who received azithromycin on top of standard prophylaxis (N Engl J Med. 2016 Sept 29;375[13]:1231-41).
“The bottom line is that, a couple of grams of cefazolin [administered before the incision] isn’t enough, especially for women with risk factors for infection. We see infection rates of more than 10% because cefazolin alone is simply inadequate. The results from both our study and the 2016 study show we can do better to reduce morbidity,” said Dr. Warshak.
“In high-risk women, such as those who are obese, we probably need to expand the spectrum and duration of prophylaxis,” agreed Dr. Main. “Obesity is one high-risk group, but there are others.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @mitchelzoler
AT THE PREGNANCY MEETING
Key clinical point:
Major finding: Surgical site infections occurred in 7% of women who received oral prophylaxis and 16% of controls during 30-day follow-up.
Data source: A single-center randomized trial with 382 evaluable women.
Disclosures: Dr. Warshak had no relevant disclosures.
New ACC guidance on periprocedural management of anticoagulation in A-fib falls short
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
In reviewing Dr. Estes’ comments on a consensus statement regarding anticoagulation bridging for patients with atrial fibrillation, the most important point is that there are minimal good data to support decision making; therefore, treatments need to be individualized to the patient. He provides a reasonable paradigm for his own decision making in these complex patients. Ultimately, until there is better evidence, the decision on whether to bridge or not to bridge patients’ anticoagulation will continue to be an individual choice based upon bleeding risk with the planned surgical procedure, potential for significant adverse outcomes if bleeding occurs, and the risk of stroke or other embolic phenomenon with cessation of anticoagulation.
Dr. Linda Harris is the division chief, vascular surgery, at the State University of New York at Buffalo and an associate editor of Vascular Specialist.
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
SNOWMASS, COLO. – The 2017 American College of Cardiology Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation is a dense, 28-page document filled with multicolored flow charts and six separate management algorithms. But this complex scheme is no substitute for practical clinical judgment and individualized decision making, N.A. Mark Estes, MD, said at the Annual Cardiovascular Conference at Snowmass.
The decision pathway attempts to guide physicians in making decisions about whether and how to interrupt anticoagulation or bridge with a parenteral agent such as low-molecular-weight heparin, and how to restart oral anticoagulation post-procedure (J Am Coll Cardiol. 2017 Jan 5; doi: 10.1016/j.jacc.2016.11.024).
The document defies concise summary. Dr. Estes chose instead to describe the approach he uses in clinical decision-making regarding anticoagulation in patients with atrial fibrillation undergoing invasive procedures. He relies upon three elements: stroke risk as assessed by CHA2DS2-VASc score; bleeding risk using the HAS-BLED score; and the inherent bleeding risk of the procedure itself.
“An important thing to remember is, any procedure done along the spinal cord or intracranially carries an extremely high risk of bleeding,” the cardiologist noted by way of example.
If a patient with atrial fibrillation has a CHA2DS2-VASc score of 2 or less, he doesn’t offer bridging regardless of the HAS-BLED score. If the stroke risk is high as defined by a CHA2DS2-VASc score of 7 or more, and the patient’s bleeding risk isn’t high, meaning the HAS-BLED score is less than 3, he seriously considers bridging, provided that the patient’s oral anticoagulant is warfarin.
“I don’t think at this point we should be bridging with the DOACs [the direct oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban]. All the available data on bridging with the DOACs indicates that it results in a high risk of bleeding with no reduction in risk of stroke,” Dr. Estes said.
The “vast majority” of patients with atrial fibrillation facing surgery have a CHA2DS2-VASc score of 3-7 and thus fall into a category where individualized consideration of the risks and benefits of bridging rules. The large, randomized, double-blind BRIDGE trial speaks to this population. In this study of atrial fibrillation patients on warfarin prior to their procedure, bridging with low-molecular-weight heparin resulted in an increased risk of major bleeding with no reduction in stroke risk compared with a temporary halt of warfarin with no bridging (N Engl J Med. 2015 Aug 27;373[9]:823-33).
“This is a no-brainer,” Dr. Estes said. “When you bridge, your patients bleed more, and you don’t reduce strokes.”
The real challenge is the type of patient who falls into what he called “the dilemma zone,” with a CHA2DS2-VASc score of 7 or more and a HAS-BLED score of 3 or higher, meaning they are at very high risk for both stroke and bleeding.
“I have a discussion with those patients. I usually do not bridge. I’m biased because of having done a lot more harm than good in bridging,” the cardiologist said.
Dr. Estes reported serving as a consultant to Boston Scientific, Medtronic, and St. Jude Medical.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Five quick ways HHS Secretary Tom Price could change the course of health policy
After a bruising confirmation process, the Senate confirmed Rep. Tom Price, R-Ga., to head up the Department of Health and Human Services, by a 52-47 vote.
As secretary, Price will have significant authority to rewrite the rules for the Affordable Care Act, some of which are reportedly nearly ready to be issued.
But there is much more now within Price’s purview, as head of an agency with a budget of more than $1 trillion for the current fiscal year. He can interpret laws in different ways than his predecessors and rewrite regulations and guidance, which is how many important policies are actually carried out.
“Virtually everything people do every day is impacted by the way the Department of Health and Human Services is run,” said Matt Myers, president of the Campaign for Tobacco-Free Kids. HHS responsibilities include food and drug safety, biomedical research, disease prevention and control, as well as oversight over everything from medical laboratories to nursing homes.
Price, a Georgia physician who opposes the Affordable Care Act, abortion, and funding for Planned Parenthood, among other things, could have a rapid impact without even a presidential order or an act of Congress.
Some advocates are excited by that possibility. “With Dr. Price taking the helm of American health policy, doctors and patients alike have sound reasons to hope for a welcome and long-overdue change,” Robert Moffit, a senior fellow at the conservative Heritage Foundation, said in a statement when Price’s nomination was announced.
Others are less enthusiastic. Asked about what policies Price might enact, Topher Spiro of the liberal Center for American Progress said at that time: “I don’t know if I want to brainstorm bad ideas for him to do.”
Here are five actions the new HHS secretary might take, according to advocates on both sides, that would disrupt health policies currently in force:
Birth control coverage: Under the ACA, most insurance plans must provide women with any form of contraception approved by the Food and Drug Administration at no additional cost. This has been particularly controversial in regards to religious employers who object to artificial contraception, leading to alterations in the rules, and resulting in two separate Supreme Court rulings, one about private firms’ rights to make religious objections, and one about nonprofit religious hospitals and schools.
As secretary, Price would have two main options. He could expand the “accommodation” that already exempts some houses of worship from the requirement to any employer with a religious objection. Or, because the specific inclusion of birth control came via a regulation rather than the law itself, he could simply eliminate no-copay birth control coverage from the benefits insurance plans must offer. (This assumes continuing existence of the health law, at least for the short term.)
Medicare payment changes: The health law created an agency within Medicare, called the Center for Medicare and Medicaid Innovation, that was tasked with exploring new ways to pay doctors and hospitals that would reduce costs while maintaining quality. The HHS secretary has the authority to require doctors and hospitals to participate in the experiments and new payment models. Some have proved unpopular with physician and hospital groups, in particular the idea of paying providers so-called bundled payments for packages of care, rather than allowing them to bill item-by-item; one such package covers hip and knee replacements, from the time of surgery through postsurgical rehabilitation. Price, as a former orthopedic surgeon himself, would likely act to scale back, delay, or cancel that project, since he “has been a critic in the past,” said Dan Mendelson, CEO of Avalere Health, a Washington-based consulting firm.
Planned Parenthood funding: Republicans have been agitating to separate Planned Parenthood from its federal funding literally for decades. Congress would have to change Medicaid law to permanently defund the women’s health group, which also performs abortions (with non-federal funds) at many of its sites. But an HHS secretary has many tools at his disposal to make life miserable for the organization.
For example, during the Reagan and George H.W. Bush administrations, rules were put in place, and eventually upheld by the Supreme Court, that would have banned staff in federally funded family planning clinics from counseling or referring for abortion women with unintended pregnancies. The subsequent Clinton administration repealed the rules, but they could make a comeback under the new secretary’s leadership.
Price could also throw the weight of the department into a probe into Planned Parenthood’s ties to firms allegedly selling fetal tissue for profit, which has also been investigated by a House committee.
Tobacco regulation: After years of discord, Congress finally agreed to give the Food and Drug Administration (limited) authority to regulate tobacco products in 2009. “The core authority is statutory,” said Matt Myers of the Campaign for Tobacco-Free Kids, who advocated for the law. That means Congress would have to act to eliminate many of its changes. But a secretary who opposes the law (Price voted against it at the time) could weaken enforcement, says Myers. Or he could rewrite and water down some rules, including recent ones affecting cigars and e-cigarettes.
“The secretary has very broad discretionary authority not to vigorously enforce or implement the statute in an aggressive manner,” Myers said.
Conscience protections: At the very end of the George W. Bush administration, HHS issued rules intended to clarify that health care professionals did not have to participate in performing abortions, sterilizations, or other procedures that violated a “religious belief or moral conviction.”
Opponents of the rules complained, however, that they were so vague and sweeping that they could apply not just to opponents of abortion, but also to those who don’t want to provide birth control to unmarried women, or HIV treatment to homosexuals.
The Obama administration revised the rules dramatically, much to the continuing consternation of conservatives. They were among the few health-related items included in the health section of Trump’s website before he was inaugurated and the page was taken down. “The Administration will act to protect individual conscience in health care,” it said. Many expect the rules to be reinstated in their original form.
This is an updated version of a story that initially ran Dec. 9, 2016. It was updated Feb. 10, 2017 to reflect that Tom Price had been confirmed by the Senate.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
After a bruising confirmation process, the Senate confirmed Rep. Tom Price, R-Ga., to head up the Department of Health and Human Services, by a 52-47 vote.
As secretary, Price will have significant authority to rewrite the rules for the Affordable Care Act, some of which are reportedly nearly ready to be issued.
But there is much more now within Price’s purview, as head of an agency with a budget of more than $1 trillion for the current fiscal year. He can interpret laws in different ways than his predecessors and rewrite regulations and guidance, which is how many important policies are actually carried out.
“Virtually everything people do every day is impacted by the way the Department of Health and Human Services is run,” said Matt Myers, president of the Campaign for Tobacco-Free Kids. HHS responsibilities include food and drug safety, biomedical research, disease prevention and control, as well as oversight over everything from medical laboratories to nursing homes.
Price, a Georgia physician who opposes the Affordable Care Act, abortion, and funding for Planned Parenthood, among other things, could have a rapid impact without even a presidential order or an act of Congress.
Some advocates are excited by that possibility. “With Dr. Price taking the helm of American health policy, doctors and patients alike have sound reasons to hope for a welcome and long-overdue change,” Robert Moffit, a senior fellow at the conservative Heritage Foundation, said in a statement when Price’s nomination was announced.
Others are less enthusiastic. Asked about what policies Price might enact, Topher Spiro of the liberal Center for American Progress said at that time: “I don’t know if I want to brainstorm bad ideas for him to do.”
Here are five actions the new HHS secretary might take, according to advocates on both sides, that would disrupt health policies currently in force:
Birth control coverage: Under the ACA, most insurance plans must provide women with any form of contraception approved by the Food and Drug Administration at no additional cost. This has been particularly controversial in regards to religious employers who object to artificial contraception, leading to alterations in the rules, and resulting in two separate Supreme Court rulings, one about private firms’ rights to make religious objections, and one about nonprofit religious hospitals and schools.
As secretary, Price would have two main options. He could expand the “accommodation” that already exempts some houses of worship from the requirement to any employer with a religious objection. Or, because the specific inclusion of birth control came via a regulation rather than the law itself, he could simply eliminate no-copay birth control coverage from the benefits insurance plans must offer. (This assumes continuing existence of the health law, at least for the short term.)
Medicare payment changes: The health law created an agency within Medicare, called the Center for Medicare and Medicaid Innovation, that was tasked with exploring new ways to pay doctors and hospitals that would reduce costs while maintaining quality. The HHS secretary has the authority to require doctors and hospitals to participate in the experiments and new payment models. Some have proved unpopular with physician and hospital groups, in particular the idea of paying providers so-called bundled payments for packages of care, rather than allowing them to bill item-by-item; one such package covers hip and knee replacements, from the time of surgery through postsurgical rehabilitation. Price, as a former orthopedic surgeon himself, would likely act to scale back, delay, or cancel that project, since he “has been a critic in the past,” said Dan Mendelson, CEO of Avalere Health, a Washington-based consulting firm.
Planned Parenthood funding: Republicans have been agitating to separate Planned Parenthood from its federal funding literally for decades. Congress would have to change Medicaid law to permanently defund the women’s health group, which also performs abortions (with non-federal funds) at many of its sites. But an HHS secretary has many tools at his disposal to make life miserable for the organization.
For example, during the Reagan and George H.W. Bush administrations, rules were put in place, and eventually upheld by the Supreme Court, that would have banned staff in federally funded family planning clinics from counseling or referring for abortion women with unintended pregnancies. The subsequent Clinton administration repealed the rules, but they could make a comeback under the new secretary’s leadership.
Price could also throw the weight of the department into a probe into Planned Parenthood’s ties to firms allegedly selling fetal tissue for profit, which has also been investigated by a House committee.
Tobacco regulation: After years of discord, Congress finally agreed to give the Food and Drug Administration (limited) authority to regulate tobacco products in 2009. “The core authority is statutory,” said Matt Myers of the Campaign for Tobacco-Free Kids, who advocated for the law. That means Congress would have to act to eliminate many of its changes. But a secretary who opposes the law (Price voted against it at the time) could weaken enforcement, says Myers. Or he could rewrite and water down some rules, including recent ones affecting cigars and e-cigarettes.
“The secretary has very broad discretionary authority not to vigorously enforce or implement the statute in an aggressive manner,” Myers said.
Conscience protections: At the very end of the George W. Bush administration, HHS issued rules intended to clarify that health care professionals did not have to participate in performing abortions, sterilizations, or other procedures that violated a “religious belief or moral conviction.”
Opponents of the rules complained, however, that they were so vague and sweeping that they could apply not just to opponents of abortion, but also to those who don’t want to provide birth control to unmarried women, or HIV treatment to homosexuals.
The Obama administration revised the rules dramatically, much to the continuing consternation of conservatives. They were among the few health-related items included in the health section of Trump’s website before he was inaugurated and the page was taken down. “The Administration will act to protect individual conscience in health care,” it said. Many expect the rules to be reinstated in their original form.
This is an updated version of a story that initially ran Dec. 9, 2016. It was updated Feb. 10, 2017 to reflect that Tom Price had been confirmed by the Senate.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
After a bruising confirmation process, the Senate confirmed Rep. Tom Price, R-Ga., to head up the Department of Health and Human Services, by a 52-47 vote.
As secretary, Price will have significant authority to rewrite the rules for the Affordable Care Act, some of which are reportedly nearly ready to be issued.
But there is much more now within Price’s purview, as head of an agency with a budget of more than $1 trillion for the current fiscal year. He can interpret laws in different ways than his predecessors and rewrite regulations and guidance, which is how many important policies are actually carried out.
“Virtually everything people do every day is impacted by the way the Department of Health and Human Services is run,” said Matt Myers, president of the Campaign for Tobacco-Free Kids. HHS responsibilities include food and drug safety, biomedical research, disease prevention and control, as well as oversight over everything from medical laboratories to nursing homes.
Price, a Georgia physician who opposes the Affordable Care Act, abortion, and funding for Planned Parenthood, among other things, could have a rapid impact without even a presidential order or an act of Congress.
Some advocates are excited by that possibility. “With Dr. Price taking the helm of American health policy, doctors and patients alike have sound reasons to hope for a welcome and long-overdue change,” Robert Moffit, a senior fellow at the conservative Heritage Foundation, said in a statement when Price’s nomination was announced.
Others are less enthusiastic. Asked about what policies Price might enact, Topher Spiro of the liberal Center for American Progress said at that time: “I don’t know if I want to brainstorm bad ideas for him to do.”
Here are five actions the new HHS secretary might take, according to advocates on both sides, that would disrupt health policies currently in force:
Birth control coverage: Under the ACA, most insurance plans must provide women with any form of contraception approved by the Food and Drug Administration at no additional cost. This has been particularly controversial in regards to religious employers who object to artificial contraception, leading to alterations in the rules, and resulting in two separate Supreme Court rulings, one about private firms’ rights to make religious objections, and one about nonprofit religious hospitals and schools.
As secretary, Price would have two main options. He could expand the “accommodation” that already exempts some houses of worship from the requirement to any employer with a religious objection. Or, because the specific inclusion of birth control came via a regulation rather than the law itself, he could simply eliminate no-copay birth control coverage from the benefits insurance plans must offer. (This assumes continuing existence of the health law, at least for the short term.)
Medicare payment changes: The health law created an agency within Medicare, called the Center for Medicare and Medicaid Innovation, that was tasked with exploring new ways to pay doctors and hospitals that would reduce costs while maintaining quality. The HHS secretary has the authority to require doctors and hospitals to participate in the experiments and new payment models. Some have proved unpopular with physician and hospital groups, in particular the idea of paying providers so-called bundled payments for packages of care, rather than allowing them to bill item-by-item; one such package covers hip and knee replacements, from the time of surgery through postsurgical rehabilitation. Price, as a former orthopedic surgeon himself, would likely act to scale back, delay, or cancel that project, since he “has been a critic in the past,” said Dan Mendelson, CEO of Avalere Health, a Washington-based consulting firm.
Planned Parenthood funding: Republicans have been agitating to separate Planned Parenthood from its federal funding literally for decades. Congress would have to change Medicaid law to permanently defund the women’s health group, which also performs abortions (with non-federal funds) at many of its sites. But an HHS secretary has many tools at his disposal to make life miserable for the organization.
For example, during the Reagan and George H.W. Bush administrations, rules were put in place, and eventually upheld by the Supreme Court, that would have banned staff in federally funded family planning clinics from counseling or referring for abortion women with unintended pregnancies. The subsequent Clinton administration repealed the rules, but they could make a comeback under the new secretary’s leadership.
Price could also throw the weight of the department into a probe into Planned Parenthood’s ties to firms allegedly selling fetal tissue for profit, which has also been investigated by a House committee.
Tobacco regulation: After years of discord, Congress finally agreed to give the Food and Drug Administration (limited) authority to regulate tobacco products in 2009. “The core authority is statutory,” said Matt Myers of the Campaign for Tobacco-Free Kids, who advocated for the law. That means Congress would have to act to eliminate many of its changes. But a secretary who opposes the law (Price voted against it at the time) could weaken enforcement, says Myers. Or he could rewrite and water down some rules, including recent ones affecting cigars and e-cigarettes.
“The secretary has very broad discretionary authority not to vigorously enforce or implement the statute in an aggressive manner,” Myers said.
Conscience protections: At the very end of the George W. Bush administration, HHS issued rules intended to clarify that health care professionals did not have to participate in performing abortions, sterilizations, or other procedures that violated a “religious belief or moral conviction.”
Opponents of the rules complained, however, that they were so vague and sweeping that they could apply not just to opponents of abortion, but also to those who don’t want to provide birth control to unmarried women, or HIV treatment to homosexuals.
The Obama administration revised the rules dramatically, much to the continuing consternation of conservatives. They were among the few health-related items included in the health section of Trump’s website before he was inaugurated and the page was taken down. “The Administration will act to protect individual conscience in health care,” it said. Many expect the rules to be reinstated in their original form.
This is an updated version of a story that initially ran Dec. 9, 2016. It was updated Feb. 10, 2017 to reflect that Tom Price had been confirmed by the Senate.
Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation.
Doctors, drug reps, and free speech
Question: The First Amendment guarantees the right of free speech, but the U.S. Supreme Court has held that under a strict scrutiny standard, the government may regulate:
A. Obscenity.
B. Fighting words.
C. Professional speech.
D. A and B.
E. A, B, and C.
Answer: D. The First Amendment forbids the government from “abridging the freedom of speech,” which extends to certain nonverbal conduct, such as flag burning. At the same time, the U.S. Supreme Court has also ruled that certain categories of speech such as obscenity and fighting words can be regulated under a strict scrutiny standard. However, it remains unsettled whether and to what extent professional speech – such as in the context of the doctor-patient relationship – may be curtailed.
Two recent cases grapple with this issue of free speech – with rather unexpected results.
The first, overturning a decades-old prohibition of the off-label detailing of drugs, surprisingly was decided against the government. The second challenges a Florida statute censoring the discussion of firearms safety between a doctor and a patient. An early decision, under reconsideration, in fact supported the state’s regulation of physicians’ freedom of speech under the circumstances.
Because the FDA has no jurisdiction over physician conduct, it has no power to regulate the off-label use of an otherwise approved drug, which explains why such off-label prescriptions are widespread, especially in the oncology field.
In U.S. v. Caronia, the defendant, a pharmaceutical sales representative, was criminally prosecuted and found guilty of conspiracy in a New York court for introducing a misbranded drug into interstate commerce.1 Specifically, Alfred Caronia promoted the drug Xyrem for use in a manner not approved by the FDA.
Orphan Medical, now known as Jazz Pharmaceuticals, is the manufacturer of Xyrem, a powerful central nervous system depressant. Xyrem’s active ingredient is gamma-hydroxybutyrate, which has been federally classified as the “date rape drug” for its use in the commission of sexual assaults. The FDA had approved Xyrem for two conditions: to treat narcolepsy patients who experience cataplexy, a condition associated with weak or paralyzed muscles; and to treat those with excessive daytime sleepiness.
Caronia was found to provide off-label detailing of the drug to doctors for unapproved indications such as chronic fatigue, fibromyalgia, restless leg syndrome, and Parkinson’s disease.
Caronia argued that in promoting an FDA-approved drug, albeit for off-label use, he was within his right of free speech under the First Amendment. In overturning his conviction, a three-judge panel of the U.S. Second Circuit Court of Appeals agreed, noting the overly broad FDA regulations and specifically that nothing Caronia did constituted conspiracy to put a false or misleading or deficient label on a drug product.
The court concluded: “The government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA [Federal Food, Drug, and Cosmetic Act] for speech promoting the lawful, off-label use of an FDA-approved drug.”
In 2011, the U.S. Supreme Court had used a First Amendment argument to invalidate a Vermont law that prohibited the practice of pharmaceutical data mining – purchasing information about prescribers from pharmacies and others.2
Taken together, the FDA now appears resigned to the free speech argument.3 For example, it has decided not to appeal a judge’s ruling that the First Amendment protects Amarin from promoting its fish-oil capsules for unapproved uses. Just recently, the FDA published a draft proposal in tacit acceptance of this new policy position, merely recommending the disclosure of relevant information including limitations and unfavorable or inconsistent findings surrounding the off-label use of a drug.
The next issue concerns professional speech. It is well documented that the presence of a gun in the home increases the risk of death especially by suicide, and this serves as the impetus for the long-established recommendation that physicians discuss firearm safety with their patients.
The medical profession was therefore aghast when Florida enacted its law on “Privacy of Firearm Owners.”4 Codified on June 2, 2011, it provides that a licensed practitioner or facility may not record firearm ownership information in a patient’s medical record, and that unless information is relevant to the patient’s medical care or safety or safety of others, inquiries regarding firearm ownership or possession should not be made. A practitioner is also forbidden from unnecessarily harassing a patient about firearm ownership during an examination.
Violation can result in disciplinary action; the original intent was to make this a third-degree felony with penalties of up to $5 million in fines and 5 years of imprisonment, but the final bill was stripped of criminal penalties.
In July 2015, a panel of three judges of the U.S. 11th Circuit Court of Appeals, in a split 2-1 decision, found that the inquiry, record-keeping, and harassment provisions of the act specifically regulate professional speech, which is subject to an intermediate level of scrutiny. Under this level of scrutiny, the court found that the act was precisely tailored to directly advance the state’s substantial interests in protecting the public and patient privacy rights.
Holding that the act was not so overly broad as to violate the First Amendment, the court ruled that laws regulating speech that occurs in the course of the physician-patient relationship are constitutional if they directly advance a substantial state interest.5
Predictably, several medical societies, including the AMA, have filed briefs arguing that the law is unconstitutional and intrudes on the practice of medicine. Effective medical care is believed to require “unfettered communications” between physicians and their patients. Besides, the law is at odds with the AMA’s longstanding policy that encourages members to inquire into the presence of firearms in households and to promote the use of safety locks on guns in an effort to reduce injuries to children.
On June 21, 2016, the full 11th Circuit Court of Appeals (sitting “en banc”) heard arguments, and the profession eagerly awaits its final opinion.
Meanwhile, commentators have expressed concerns that such laws threaten the sanctity of the physician-patient relationship, which relies on truthful communication to freely counsel patients.
This infringement may be gathering force. Missouri and Montana already have similar gun privacy laws, while other states have required physicians to keep confidential any information regarding chemicals used in fracking, or mandate the provision of various birth-related information prior to a woman’s decision to have an abortion.6
References
1. U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012).
2. Sorrell v. IMS Health, 131 S. Ct. 2653 (2011).
3. N Engl J Med. 2013 Jan 10;368(2):103-5.
4. Fla. St. 381.026, 456.072, 790.338.
5. Wollschlaeger v. Governor of Florida, 797 F.3d 859 (11th Cir. 2015).
6. N Engl J Med. 2016 Jun 16;374(24):2304-7.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Question: The First Amendment guarantees the right of free speech, but the U.S. Supreme Court has held that under a strict scrutiny standard, the government may regulate:
A. Obscenity.
B. Fighting words.
C. Professional speech.
D. A and B.
E. A, B, and C.
Answer: D. The First Amendment forbids the government from “abridging the freedom of speech,” which extends to certain nonverbal conduct, such as flag burning. At the same time, the U.S. Supreme Court has also ruled that certain categories of speech such as obscenity and fighting words can be regulated under a strict scrutiny standard. However, it remains unsettled whether and to what extent professional speech – such as in the context of the doctor-patient relationship – may be curtailed.
Two recent cases grapple with this issue of free speech – with rather unexpected results.
The first, overturning a decades-old prohibition of the off-label detailing of drugs, surprisingly was decided against the government. The second challenges a Florida statute censoring the discussion of firearms safety between a doctor and a patient. An early decision, under reconsideration, in fact supported the state’s regulation of physicians’ freedom of speech under the circumstances.
Because the FDA has no jurisdiction over physician conduct, it has no power to regulate the off-label use of an otherwise approved drug, which explains why such off-label prescriptions are widespread, especially in the oncology field.
In U.S. v. Caronia, the defendant, a pharmaceutical sales representative, was criminally prosecuted and found guilty of conspiracy in a New York court for introducing a misbranded drug into interstate commerce.1 Specifically, Alfred Caronia promoted the drug Xyrem for use in a manner not approved by the FDA.
Orphan Medical, now known as Jazz Pharmaceuticals, is the manufacturer of Xyrem, a powerful central nervous system depressant. Xyrem’s active ingredient is gamma-hydroxybutyrate, which has been federally classified as the “date rape drug” for its use in the commission of sexual assaults. The FDA had approved Xyrem for two conditions: to treat narcolepsy patients who experience cataplexy, a condition associated with weak or paralyzed muscles; and to treat those with excessive daytime sleepiness.
Caronia was found to provide off-label detailing of the drug to doctors for unapproved indications such as chronic fatigue, fibromyalgia, restless leg syndrome, and Parkinson’s disease.
Caronia argued that in promoting an FDA-approved drug, albeit for off-label use, he was within his right of free speech under the First Amendment. In overturning his conviction, a three-judge panel of the U.S. Second Circuit Court of Appeals agreed, noting the overly broad FDA regulations and specifically that nothing Caronia did constituted conspiracy to put a false or misleading or deficient label on a drug product.
The court concluded: “The government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA [Federal Food, Drug, and Cosmetic Act] for speech promoting the lawful, off-label use of an FDA-approved drug.”
In 2011, the U.S. Supreme Court had used a First Amendment argument to invalidate a Vermont law that prohibited the practice of pharmaceutical data mining – purchasing information about prescribers from pharmacies and others.2
Taken together, the FDA now appears resigned to the free speech argument.3 For example, it has decided not to appeal a judge’s ruling that the First Amendment protects Amarin from promoting its fish-oil capsules for unapproved uses. Just recently, the FDA published a draft proposal in tacit acceptance of this new policy position, merely recommending the disclosure of relevant information including limitations and unfavorable or inconsistent findings surrounding the off-label use of a drug.
The next issue concerns professional speech. It is well documented that the presence of a gun in the home increases the risk of death especially by suicide, and this serves as the impetus for the long-established recommendation that physicians discuss firearm safety with their patients.
The medical profession was therefore aghast when Florida enacted its law on “Privacy of Firearm Owners.”4 Codified on June 2, 2011, it provides that a licensed practitioner or facility may not record firearm ownership information in a patient’s medical record, and that unless information is relevant to the patient’s medical care or safety or safety of others, inquiries regarding firearm ownership or possession should not be made. A practitioner is also forbidden from unnecessarily harassing a patient about firearm ownership during an examination.
Violation can result in disciplinary action; the original intent was to make this a third-degree felony with penalties of up to $5 million in fines and 5 years of imprisonment, but the final bill was stripped of criminal penalties.
In July 2015, a panel of three judges of the U.S. 11th Circuit Court of Appeals, in a split 2-1 decision, found that the inquiry, record-keeping, and harassment provisions of the act specifically regulate professional speech, which is subject to an intermediate level of scrutiny. Under this level of scrutiny, the court found that the act was precisely tailored to directly advance the state’s substantial interests in protecting the public and patient privacy rights.
Holding that the act was not so overly broad as to violate the First Amendment, the court ruled that laws regulating speech that occurs in the course of the physician-patient relationship are constitutional if they directly advance a substantial state interest.5
Predictably, several medical societies, including the AMA, have filed briefs arguing that the law is unconstitutional and intrudes on the practice of medicine. Effective medical care is believed to require “unfettered communications” between physicians and their patients. Besides, the law is at odds with the AMA’s longstanding policy that encourages members to inquire into the presence of firearms in households and to promote the use of safety locks on guns in an effort to reduce injuries to children.
On June 21, 2016, the full 11th Circuit Court of Appeals (sitting “en banc”) heard arguments, and the profession eagerly awaits its final opinion.
Meanwhile, commentators have expressed concerns that such laws threaten the sanctity of the physician-patient relationship, which relies on truthful communication to freely counsel patients.
This infringement may be gathering force. Missouri and Montana already have similar gun privacy laws, while other states have required physicians to keep confidential any information regarding chemicals used in fracking, or mandate the provision of various birth-related information prior to a woman’s decision to have an abortion.6
References
1. U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012).
2. Sorrell v. IMS Health, 131 S. Ct. 2653 (2011).
3. N Engl J Med. 2013 Jan 10;368(2):103-5.
4. Fla. St. 381.026, 456.072, 790.338.
5. Wollschlaeger v. Governor of Florida, 797 F.3d 859 (11th Cir. 2015).
6. N Engl J Med. 2016 Jun 16;374(24):2304-7.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Question: The First Amendment guarantees the right of free speech, but the U.S. Supreme Court has held that under a strict scrutiny standard, the government may regulate:
A. Obscenity.
B. Fighting words.
C. Professional speech.
D. A and B.
E. A, B, and C.
Answer: D. The First Amendment forbids the government from “abridging the freedom of speech,” which extends to certain nonverbal conduct, such as flag burning. At the same time, the U.S. Supreme Court has also ruled that certain categories of speech such as obscenity and fighting words can be regulated under a strict scrutiny standard. However, it remains unsettled whether and to what extent professional speech – such as in the context of the doctor-patient relationship – may be curtailed.
Two recent cases grapple with this issue of free speech – with rather unexpected results.
The first, overturning a decades-old prohibition of the off-label detailing of drugs, surprisingly was decided against the government. The second challenges a Florida statute censoring the discussion of firearms safety between a doctor and a patient. An early decision, under reconsideration, in fact supported the state’s regulation of physicians’ freedom of speech under the circumstances.
Because the FDA has no jurisdiction over physician conduct, it has no power to regulate the off-label use of an otherwise approved drug, which explains why such off-label prescriptions are widespread, especially in the oncology field.
In U.S. v. Caronia, the defendant, a pharmaceutical sales representative, was criminally prosecuted and found guilty of conspiracy in a New York court for introducing a misbranded drug into interstate commerce.1 Specifically, Alfred Caronia promoted the drug Xyrem for use in a manner not approved by the FDA.
Orphan Medical, now known as Jazz Pharmaceuticals, is the manufacturer of Xyrem, a powerful central nervous system depressant. Xyrem’s active ingredient is gamma-hydroxybutyrate, which has been federally classified as the “date rape drug” for its use in the commission of sexual assaults. The FDA had approved Xyrem for two conditions: to treat narcolepsy patients who experience cataplexy, a condition associated with weak or paralyzed muscles; and to treat those with excessive daytime sleepiness.
Caronia was found to provide off-label detailing of the drug to doctors for unapproved indications such as chronic fatigue, fibromyalgia, restless leg syndrome, and Parkinson’s disease.
Caronia argued that in promoting an FDA-approved drug, albeit for off-label use, he was within his right of free speech under the First Amendment. In overturning his conviction, a three-judge panel of the U.S. Second Circuit Court of Appeals agreed, noting the overly broad FDA regulations and specifically that nothing Caronia did constituted conspiracy to put a false or misleading or deficient label on a drug product.
The court concluded: “The government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA [Federal Food, Drug, and Cosmetic Act] for speech promoting the lawful, off-label use of an FDA-approved drug.”
In 2011, the U.S. Supreme Court had used a First Amendment argument to invalidate a Vermont law that prohibited the practice of pharmaceutical data mining – purchasing information about prescribers from pharmacies and others.2
Taken together, the FDA now appears resigned to the free speech argument.3 For example, it has decided not to appeal a judge’s ruling that the First Amendment protects Amarin from promoting its fish-oil capsules for unapproved uses. Just recently, the FDA published a draft proposal in tacit acceptance of this new policy position, merely recommending the disclosure of relevant information including limitations and unfavorable or inconsistent findings surrounding the off-label use of a drug.
The next issue concerns professional speech. It is well documented that the presence of a gun in the home increases the risk of death especially by suicide, and this serves as the impetus for the long-established recommendation that physicians discuss firearm safety with their patients.
The medical profession was therefore aghast when Florida enacted its law on “Privacy of Firearm Owners.”4 Codified on June 2, 2011, it provides that a licensed practitioner or facility may not record firearm ownership information in a patient’s medical record, and that unless information is relevant to the patient’s medical care or safety or safety of others, inquiries regarding firearm ownership or possession should not be made. A practitioner is also forbidden from unnecessarily harassing a patient about firearm ownership during an examination.
Violation can result in disciplinary action; the original intent was to make this a third-degree felony with penalties of up to $5 million in fines and 5 years of imprisonment, but the final bill was stripped of criminal penalties.
In July 2015, a panel of three judges of the U.S. 11th Circuit Court of Appeals, in a split 2-1 decision, found that the inquiry, record-keeping, and harassment provisions of the act specifically regulate professional speech, which is subject to an intermediate level of scrutiny. Under this level of scrutiny, the court found that the act was precisely tailored to directly advance the state’s substantial interests in protecting the public and patient privacy rights.
Holding that the act was not so overly broad as to violate the First Amendment, the court ruled that laws regulating speech that occurs in the course of the physician-patient relationship are constitutional if they directly advance a substantial state interest.5
Predictably, several medical societies, including the AMA, have filed briefs arguing that the law is unconstitutional and intrudes on the practice of medicine. Effective medical care is believed to require “unfettered communications” between physicians and their patients. Besides, the law is at odds with the AMA’s longstanding policy that encourages members to inquire into the presence of firearms in households and to promote the use of safety locks on guns in an effort to reduce injuries to children.
On June 21, 2016, the full 11th Circuit Court of Appeals (sitting “en banc”) heard arguments, and the profession eagerly awaits its final opinion.
Meanwhile, commentators have expressed concerns that such laws threaten the sanctity of the physician-patient relationship, which relies on truthful communication to freely counsel patients.
This infringement may be gathering force. Missouri and Montana already have similar gun privacy laws, while other states have required physicians to keep confidential any information regarding chemicals used in fracking, or mandate the provision of various birth-related information prior to a woman’s decision to have an abortion.6
References
1. U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012).
2. Sorrell v. IMS Health, 131 S. Ct. 2653 (2011).
3. N Engl J Med. 2013 Jan 10;368(2):103-5.
4. Fla. St. 381.026, 456.072, 790.338.
5. Wollschlaeger v. Governor of Florida, 797 F.3d 859 (11th Cir. 2015).
6. N Engl J Med. 2016 Jun 16;374(24):2304-7.
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Senate confirms Price as HHS secretary
The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.
The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.
Democrats also rallied against the policies that Dr. Price advocated for when he was a U.S. House member, including dismantling the Affordable Care Act and pushing for block grants to fund Medicaid. He has also supported policies that would promote more extensive use of health savings accounts linked to high-deductible health plans, and high-risk pools to help ensure that those with pre-existing conditions are able to get insurance coverage without a need for guaranteed issue.
However, Democratic objections were not enough to cause any waver in support from Senate Republicans.
The American Medical Association “looks forward to working with Secretary Price to improve the health of our nation through policies that promote access to high-quality, affordable care, delivery innovation, and reduced regulatory burdens that helps patients and their physicians,” AMA President Andrew Gurman, MD, said in a statement.
The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.
The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.
Democrats also rallied against the policies that Dr. Price advocated for when he was a U.S. House member, including dismantling the Affordable Care Act and pushing for block grants to fund Medicaid. He has also supported policies that would promote more extensive use of health savings accounts linked to high-deductible health plans, and high-risk pools to help ensure that those with pre-existing conditions are able to get insurance coverage without a need for guaranteed issue.
However, Democratic objections were not enough to cause any waver in support from Senate Republicans.
The American Medical Association “looks forward to working with Secretary Price to improve the health of our nation through policies that promote access to high-quality, affordable care, delivery innovation, and reduced regulatory burdens that helps patients and their physicians,” AMA President Andrew Gurman, MD, said in a statement.
The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.
The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.
Democrats also rallied against the policies that Dr. Price advocated for when he was a U.S. House member, including dismantling the Affordable Care Act and pushing for block grants to fund Medicaid. He has also supported policies that would promote more extensive use of health savings accounts linked to high-deductible health plans, and high-risk pools to help ensure that those with pre-existing conditions are able to get insurance coverage without a need for guaranteed issue.
However, Democratic objections were not enough to cause any waver in support from Senate Republicans.
The American Medical Association “looks forward to working with Secretary Price to improve the health of our nation through policies that promote access to high-quality, affordable care, delivery innovation, and reduced regulatory burdens that helps patients and their physicians,” AMA President Andrew Gurman, MD, said in a statement.
Rituximab is dramatically effective in IgG4-related disease
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).
“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.
“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.
In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).
There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.
So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.
Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.
Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM