SVSConnect gives members an opportunity to share tough cases, discuss new breakthroughs in the industry and/or seek trusty advice from other professionals. Currently a post about Peer Support through the new SVS Member Support Program is one of the many discussions that users are engaging in. This post kicks off a series of discussion posts by the SVS Wellness Task Force, in collaboration with SurgeonMasters, that will focus on improving surgeons’ well-being, practice performance and patient outcomes. It is recommended that all who access SVSConnect on their mobile device download the app. This is the most user-friendly way to access the community and is an easy download. Follow the steps on this PDF to download the app. Reach out to [email protected] with any questions.

SVSConnect gives members an opportunity to share tough cases, discuss new breakthroughs in the industry and/or seek trusty advice from other professionals. Currently a post about Peer Support through the new SVS Member Support Program is one of the many discussions that users are engaging in. This post kicks off a series of discussion posts by the SVS Wellness Task Force, in collaboration with SurgeonMasters, that will focus on improving surgeons’ well-being, practice performance and patient outcomes. It is recommended that all who access SVSConnect on their mobile device download the app. This is the most user-friendly way to access the community and is an easy download. Follow the steps on this PDF to download the app. Reach out to [email protected] with any questions.

SVSConnect gives members an opportunity to share tough cases, discuss new breakthroughs in the industry and/or seek trusty advice from other professionals. Currently a post about Peer Support through the new SVS Member Support Program is one of the many discussions that users are engaging in. This post kicks off a series of discussion posts by the SVS Wellness Task Force, in collaboration with SurgeonMasters, that will focus on improving surgeons’ well-being, practice performance and patient outcomes. It is recommended that all who access SVSConnect on their mobile device download the app. This is the most user-friendly way to access the community and is an easy download. Follow the steps on this PDF to download the app. Reach out to [email protected] with any questions.

PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.

In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.

However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.

Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.

The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.

The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.

However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.

Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”

Copyright American Heart Association

Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.

GALILEO

Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.

These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.

In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.

From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).

The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).

Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.

In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).

Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).

A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).

The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”

Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.

Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”

Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.

“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.

The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.

GALILEO 4D

However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.

The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.

The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).

“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.

However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”

Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.

Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.

“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.

The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.

That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.

“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.

“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”

The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.

Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.

“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”

While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.

The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”

Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.

“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.

“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”

Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.

The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.

SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.

This article also appears on Medscape.com.

PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.

In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.

However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.

Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.

The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.

The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.

However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.

Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”

Copyright American Heart Association

Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.

GALILEO

Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.

These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.

In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.

From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).

The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).

Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.

In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).

Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).

A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).

The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”

Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.

Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”

Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.

“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.

The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.

GALILEO 4D

However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.

The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.

The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).

“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.

However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”

Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.

Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.

“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.

The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.

That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.

“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.

“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”

The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.

Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.

“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”

While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.

The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”

Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.

“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.

“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”

Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.

The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.

SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.

This article also appears on Medscape.com.

PHILADELPHIA – The results of the first randomized prospective trial of an anticoagulation strategy versus standard dual antiplatelet (DAPT) therapy for patients undergoing transcatheter aortic valve replacement (TAVR) show that routine anticoagulation is not suitable for all comers in a high-risk population.

In the main GALILEO trial of elderly patients after TAVR, those who received an investigational anticoagulation strategy with the direct factor Xa inhibitor rivaroxaban (Xarelto; Bayer/Janssen) had worse survival and more thromboembolic and bleeding events than patients who received standard DAPT.

However, in the GALILEO 4D substudy of patients who underwent four-dimensional computed tomography (4DCT) randomized to the two therapies, those in the rivaroxaban arm were less likely to show subclinical leaflet motion abnormalities and leaflet thickening.

Preliminary results from GALILEO were disclosed in an October 3, 2018, “Dear Healthcare Professional” letter from Bayer, and the trial was stopped after a median of 17 months due to safety concerns.

The full data analysis from GALILEO as well as the results from GALILEO 4D were presented at the American Heart Association scientific sessions to coincide with their publication on Nov. 16, 2019, in the New England Journal of Medicine.

The takeaway message is that, despite the positive imaging finding in GALILEO 4D, “there is no reason to give 10 mg rivaroxaban-based treatment routinely after TAVR in patients who don’t need anticoagulation anyhow,” lead author in the main GALILEO trial, George D. Dangas, MD, PhD, Mount Sinai Hospital, New York, said in an interview.

However, because rivaroxaban had an effect in reducing the clots on leaflets, he said, further investigation is required to determine the optimal therapeutic strategy after TAVR.

Similarly, the assigned discussant for GALILEO, Elaine Hylek, MD, of Boston University said in an interview that “we just don’t know right now what the overall added benefit of an oral anticoagulant would be in this high-risk patient population after having a TAVR.”

Copyright American Heart Association

Ole De Backer, MD, PhD, of Rigshospitalet University Hospital, Copenhagen, lead author of the GALILEO 4D substudy, concluded that, although the rivaroxaban-based strategy was associated with fewer valve abnormalities in this analysis, those positive outcomes need to be taken in context with worse clinical outcomes in the main GALILEO trial.

GALILEO

Guidelines recommend DAPT after TAVR, but this advice is based on expert consensus or small studies, the GALILEO study authors noted. Several years ago, there were random case reports and then case series of patients who had undergone TAVR or surgical aortic valve replacement (SAVR) and developed clots around the valve, Dr. Dangas explained.

These developments coincided with the first available high-quality CT angiography images that captured valve abnormalities that had not been seen before.

In parallel, there were rare reports of stroke and transient ischemic attack (TIA) that may have been associated with TAVR or SAVR. This triggered a series of studies to investigate an anticoagulation strategy after TAVR.

From December 2015 to May 2018, GALILEO enrolled 1,644 patients at 136 sites in 16 countries who had undergone successful TAVR, and had no indication for an anticoagulant (e.g., no atrial fibrillation).

The patients had a mean age of 80.6 years (plus or minus 6.6 years) and 49.5% were female. The median time from TAVR to randomization was 2 days (range, 0-8 days).

Half were randomized to receive an antithrombotic strategy, rivaroxaban 10 mg once daily plus aspirin 75-100 mg once daily for the first 90 days followed by rivaroxaban alone. The other half received an antiplatelet-based strategy, aspirin 75-100 mg once daily plus clopidogrel 75 mg once daily for the first 90 days followed by aspirin alone.

In the intention-to-treat analysis, death or first thromboembolic event, the primary efficacy outcome, occurred in 105 patients in the rivaroxaban group and 78 patients in the antiplatelet group (hazard ratio, 1.35; 95% CI, 1.01-1.81; P = .04).

Major, disabling, or life-threatening bleeding, the primary safety outcome, occurred in 46 and 31 patients, respectively (HR, 1.50; P = .08).

A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (HR, 1.69; 95% CI, 1.13-2.53).

The individuals who were enrolled in this study were 80 and older, Dr. Hylek pointed out. “The age in and of itself is an uncontested risk factor for everything, whether it be bleeding, embolic event, or obviously mortality.”

Although the dose was half that used to prevent stroke in patients with atrial fibrillation, perhaps a “twice-daily lower dose” might be the way to go, moving forward, she said.

Patients who did not have atrial fibrillation may have developed atrial fibrillation in the interim, and “you would have to change the dose of the rivaroxaban.”

Also, patients who may have been taking aspirin for 5 or 10 years and “survived” aspirin, who were then newly exposed to an anticoagulant, would be more likely to experience bleeding.

“I certainly wouldn’t close the door on novel anticoagulants,” she concluded. “There are still other drug trials that are out there with this TAVR population. We’ll wait for that,” and see if the results corroborate these findings.

The high-risk patients may turn out to be a potential niche group for drugs being developed to inhibit factor XIa, she speculated.

GALILEO 4D

However, despite the negative results of the overall GALILEO study, results from the substudy that used 4DCT to evaluate function of the bioprosthetic aortic valves suggested rivaroxaban may have potentially beneficial effects on valve function.

The results showed that patients on the rivaroxaban and aspirin regimen had lower rates of subclinical reduced leaflet motion and leaflet thickening than patients on the antiplatelet strategy, said Dr. De Backer, reporting on behalf of the GALILEO-4D investigators.

The substudy evaluated 205 patients who had 4DCT 90 days after TAVR. The primary substudy endpoint was at least one prosthetic valve leaflet with a grade 3 or higher motion reduction, which 2 of 97 patients in the rivaroxaban group had (2.1%) versus 11 of 101 in the antiplatelet group (10.9%, P = .01).

“This indicated an 80% greater reduction of the primary endpoint in the rivaroxaban arm,” Dr. De Backer said. The chief secondary endpoint, the proportion of patients with at least one thickened leaflet, was met by 12.4% of the rivaroxaban group and 32.4% of the antiplatelet arm, “a 60% significant reduction by rivaroxaban,” Dr. De Backer said.

However, when the 10 patients in each group who didn’t adhere to the study drug regimen were excluded, he said, “then we see no single patient had reduced leaflet motion of grade 3 or more in the rivaroxaban arm.”

Another takeaway from the substudy is the ineffectiveness of transthoracic echocardiography as opposed to 4DCT in TAVR patients. Echocardiography (ECG) failed to show any significant differences in the mean valve gradient between the treatment groups, Dr. De Backer said.

Eleven patients who didn’t have leaflet thickening (7.3%) and 7 patients who did (15.9%) showed an increase of 5 mm Hg or more in the mean valve gradient on echo. ECG also showed a similar increase in the mean valve gradient in 14 patients who had no to moderate reduced leaflet motion (grade 3 or lower, 7.7%) and in four patients (30.8) who had grade 3 or higher reduced leaflet motion.

“This basically confirms results from observational studies that transthoracic echocardiography is often not good enough to detect these phenomena,” Dr. De Backer said.

The percentages of substudy patients who had major clinical events – major bleeding, thromboembolic events, or death at 90 days – were each less than 3%, he said. “There were too few clinical events to permit any assessment of the impact of leaflet thickening or reduced leaflet motion on clinical outcomes,” he said.

That lack of clarity with regard to clinical events is one of the questions the study leaves unanswered, said discussant Victoria Delgado, MD, PhD, of Leiden University Medical Center in the Netherlands.

“With stroke or TIA, there are too few events to draw any conclusions,” she said of the substudy. “We don’t know when we need to use CT, when we need to evaluate these patients, or maybe when we should go for more advanced imaging techniques where we can see the biology of those changes in the leaflets.” Hopefully, she said, future studies provide those insights.

“CT can be more sensitive than ECG to see these subclinical changes,” she said, “but the open questions that we have are to see if there is a correlation between thrombosis rate on imaging versus the stroke rate.”

The substudy’s conclusion on ECG, however, has been borne out by previous retrospective studies, Dr. Delgado added.

Robert A. Harrington, MD, of Stanford Medicine, tried to put the seemingly conflicting findings of the main GALILEO study and the 4D substudy into context.

“There you have the disconnect between the mechanism and the clinical observation and those are sometimes difficult to reconcile because the assumption is that the mechanism leads to the clinical outcome.”

While the main study shows that routine anticoagulation after TAVR is not indicated, the findings raise questions about the risk of clots forming on bioprosthetic valves. “Yes, maybe there are clots forming on these valves, but maybe that’s not causing the bad clinical outcomes,” Dr. Harrington said.

The findings also raise questions about the use of newer anticoagulants to prevent stroke post TAVR, he said. “It appears that warfarin is better than the newer anticoagulants for reasons that aren’t entirely clear.”

Dr. Dangas, lead author of the main GALILEO trial, said the substudy results could help design future trials of even-lower doses of anticoagulation in a more selective group of TAVR patients.

“In order to decrease the clots, first of all you don’t need the full dose of anticoagulation; even a low dose may do the trick,” he said. Further investigations can evaluate the clinical significance of having a blood clot in the valve as an indication for anticoagulation versus antiplatelet therapy.

“Even though this obviously doesn’t mean you’re going to have a stroke in a year or two,” Dr. Dangas said, “could it perhaps mean that the valve is not going to have such a good durability later on?”

Perhaps future studies of anticoagulation in TAVR should concentrate on patients who actually have clotting in the valve, he said.

The trial was supported by Bayer and Janssen. Dr. Dangas reported receiving grants from Bayer during the conduct of the study, personal fees from Bayer and Janssen, grants and personal fees from Daiichi-Sankyo, and “other” funding from Medtronic outside the submitted work. Dr. De Backer reported receiving grants from Bayer during the conduct of the study and personal fees from Abbott and Boston Scientific outside the submitted work.

SOURCE: Dangas GD and De Backer O. AHA 19, Late-Breaking Science 3 session.

This article also appears on Medscape.com.

Abstracts and videos for the 2020 Vascular Annual Meeting will be accepted now through January 15. The submission process may be completed on a smartphone or tablet computer. The Video Committee encourages submissions in areas such as dialysis access, lower extremity revascularization, surgical bypass procedures, venous interventions, management of adverse events and more. Read more and begin the submission process here.

Abstracts and videos for the 2020 Vascular Annual Meeting will be accepted now through January 15. The submission process may be completed on a smartphone or tablet computer. The Video Committee encourages submissions in areas such as dialysis access, lower extremity revascularization, surgical bypass procedures, venous interventions, management of adverse events and more. Read more and begin the submission process here.

Abstracts and videos for the 2020 Vascular Annual Meeting will be accepted now through January 15. The submission process may be completed on a smartphone or tablet computer. The Video Committee encourages submissions in areas such as dialysis access, lower extremity revascularization, surgical bypass procedures, venous interventions, management of adverse events and more. Read more and begin the submission process here.

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

[email protected]

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

[email protected]

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

[email protected]

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

A 47-year-old woman was referred to the gynecology office by her primary care NP for surgical excision of an enlarging nodule on the right side of her mons pubis. Onset occurred about 6 months earlier. The patient reported that symptoms waxed and waned but had worsened progressively over the past 2 to 3 months, adding that the nodule hurt only occasionally. She noted that symptoms were exacerbated by exercise, specifically running. Further questioning prompted the observation that her symptoms were more noticeable at the time of menses.

The patient’s medical history was unremarkable, with no chronic conditions; her surgical history consisted of a wisdom tooth extraction. She had no known drug allergies. Her family history included cerebrovascular accident, hypertension, and arthritis. Reproductive history revealed that she was G1 P1, with a 38-week uncomplicated vaginal delivery. She experienced menarche at age 14, and her menses was regular at every 28 days. For the past 5 days, there had been no dysmenorrhea. The patient was married, exercised regularly, and did not use tobacco, alcohol, or illicit drugs.

On examination, the patient’s blood pressure was 123/73 mm Hg; heart rate, 77 beats/min; respiratory rate, 12 breaths/min; weight, 128 lb; height, 5 ft 7 in; O₂ saturation, 99% on room air; and BMI, 20. The patient was alert and oriented to person, place, and time. She was thin, appeared physically fit, and exhibited no signs of distress. Her physical exam was unremarkable, apart from a firm, minimally tender, well-circumscribed, 3.5 × 3.5–cm nodule right of midline on the mons pubis.

The patient was scheduled for outpatient surgical excision of a benign skin lesion (excluding skin tags) of the genitalia, 3.1 to 3.5 cm (CPT code 11424). During this procedure, it became evident that this was not a lipoma. The lesion was exceptionally hard, and it was difficult to discern if it was incorporated into the rectus abdominis near the point of attachment to the pubic symphysis. The lesion was unintentionally disrupted, revealing black powdery material within the capsule. The tissue was sent for a fast, frozen section that showed “soft tissue with extensive involvement by endometriosis.” The pathology report noted “[m]any endometrial glands in a background of stromal tissue. Necrosis was not a feature. No evidence of atypia.” The patient’s postoperative diagnosis was endometriosis.

DISCUSSION

Endometriosis occurs when endometrial or “endometrial-like” tissue is displaced to sites other than within the uterus. It is most frequently found on tissues close to the uterus, such as the ovaries or pelvic peritoneum. Estrogen is the driving force that feeds the endometrium, causing it to proliferate, whether inside or outside the uterus. Given this dependence on hormones, endometriosis occurs most often during a woman’s fertile years, although it can occur after menopause. Endometriosis is common, affecting at least 10% of premenopausal women; moreover, it is identified as the cause in 70% of all female chronic pelvic pain cases.^1-4

Endometriosis has certain identifiable features, such as chronic pain, dyspareunia, infertility, and menstrual and gastrointestinal symptoms. However, it is seldom diagnosed quickly; studies indicate that diagnosis can be delayed by 5 to 10 years after a patient has first sought treatment for symptoms.^2,4 Multiple factors contribute to a lag in diagnosis: Presentation is not always straightforward. There are no definitive lab values or biomarkers. Symptoms vary from patient to patient, as do clinical skills from one diagnostician to another.¹

Unlike pelvic endometriosis, inguinal endometriosis is not common; disease in this location encompasses only 0.3% to 0.6% of all diagnosed cases.^3,5-7 Since the discovery of the first known case of round ligament endometriosis in 1896, there have been only 70 cases reported in the medical literature.^6,7

If the more common form of endometriosis is frequently missed, this rarely seen variant presents an even greater diagnostic challenge. The typical presentation of inguinal endometriosis includes a firm nodule in the groin, accompanied by tenderness and swelling. A careful history will allude to pain that occurs cyclically with menses.

Cause

Among several theories about the etiology of endometriosis, the most popular has been retrograde menstruation.^1,4,5 According to this hypothesis, the flow of menstrual blood moves backward through the fallopian tubes, spilling into the pelvic cavity and carrying endometrial tissue with it. One theory purports that endometrial tissue is transplanted from the uterus to other areas of the body via the bloodstream or the lymphatics, much like a metastatic disease.^1,4 Another theory states that cells outside the uterus, which line the peritoneum, transform into endometrial cells through metaplasia.^4,5 Endometrial tissue can also be transplanted iatrogenically during surgery—for example, when endometrial tissue is displaced during a cesarean delivery, resulting in implants above the fascia and below the subcutaneous layers. Several other hypotheses concern stem-cell involvement, hormonal factors, immune system dysfunction, and genetics.^4,5 Currently, there are no definitive answers.

Location

During maturation, the parietal peritoneum develops a pouch called the processus vaginalis, which serves as a passageway for the gubernaculum to transport the round ligament running from the uterus, through the inguinal canal, and ending at the labia. After these structures reach their destination, in normal development, the processus vaginalis degenerates, closing the inguinal canal. Occasionally the processus vaginalis fails to close, allowing for a communication pathway between the peritoneal cavity and the inguinal canal. This leaves the canal vulnerable to the contents of the pelvic cavity, such as a hernia or hydrocele, and provides a clear path for endometriosis.^5-7 The implant found in the case patient was at the point where the external ring lies, just above the right pubic tubercle (see Figure 1).

Endometriosis implants can occur anywhere along the round ligament in either the intrapelvic or extrapelvic segments. Implants have also been found in the wall of a hernia sac, the wall of a Nuck canal hydrocele, or even in the subcutaneous tissue surrounding the inguinal canal.³ Interestingly, inguinal endometriosis occurs more often in the right side (up to 94% of cases) than in the left side, as was the case with our patient.^5-7 The reason for this predominance has not been established, although there are several theories, including one that suggests the left side is afforded protection by the sigmoid colon.^5-7

Laboratory diagnosis

Imaging, such as ultrasound and MRI, offers some diagnostic benefit, although its usefulness is most often realized in the pelvis. Pelvic ultrasound can be used to identify ovarian endometriomas.¹ MRI can help rule out, locate, or sometimes determine the degree of deep infiltrating endometriosis, which is an indispensable tool for surgical planning.^5,7 Unfortunately, the diagnostic accuracy for extra-pelvic lesions is variable; neither modality is particularly useful in identifying superficial lesions, which comprises most cases.

Ultrasound of the groin can be employed to evaluate for hernia; if a hernia has been excluded, histologic confirmation can be obtained via fine-needle aspiration of nodule contents.^5,7 One caveat is that these tests are helpful only if the clinician suspects the diagnosis and orders them. The definitive diagnostic test remains direct visualization, which requires laparoscopy.^1,5

Differential diagnosis

Lipoma was a favored diagnosis in this case because of the palpable, well-circumscribed borders, nontender on exam; intermittent, minimal tenderness; and no evidence of erythema or color change. A second possibility was an enlarged lymph node, which was less likely due to the location, large size, and sudden onset without any accompanying symptoms of infection or chronic illness. Finally, an inguinal hernia was least likely, again because of well-defined borders, no history of a lump in the area, a nodule that was not reducible, only minimal tenderness, and no color changes on the skin.

Management

Definitive treatment for inguinal endometriosis entails complete surgical excision.^5-7 The provider should be prepared to repair a defect after the excision; there is potential for a substantial defect that might require mesh. Additionally, a herniorrhaphy may be indicated if there is a coexisting hernia.⁵ The risk for recurrent disease in the inguinal canal after treatment is uncommon, unless the excision was not complete.³

There is an association between inguinal and pelvic endometriosis but not a direct correlation. Data on concomitant pelvic and inguinal endometriosis have been variable. In one case series of 9 patients diagnosed with inguinal endometriosis, none had a history of pelvic endometriosis, and only 1 was subsequently diagnosed with pelvic endometriosis.⁷ An increased association was noted for patients with implants found on the proximal segment of the round ligament.⁷ However, implants on the extrapelvic segment were not likely to represent pelvic disease but rather isolated lesions in the canal.⁷ For those with pelvic endometriosis, complications and recurrence are likely, resulting in the need for long-term treatment.

There is some debate in the literature whether to proceed with laparoscopy once inguinal endometriosis has been identified. Diagnostic laparoscopy to evaluate the pelvis is indicated for symptomatic patients or for cases in which an indirect inguinal hernia is suspected.⁵ Laparoscopy can offer the benefit of both a diagnostic tool and a mechanism for treatment. However, this is an invasive procedure that also incurs risks. The medical provider, in discussion with the patient, must weigh the risks against the benefits of an invasive procedure before determining how to proceed.

The lesion was excised completely. Since the patient had been entirely asymptomatic until age 47, and the risks of a potentially unnecessary surgery outweighed the theoretical benefits, the decision was made not to perform a diagnostic laparoscopy to investigate for pelvic endometriosis. The patient made a complete and uneventful recovery. No further treatment was initiated. She continues to be asymptomatic, denying any menstrual complaints, dyspareunia, or further problems with the groin.

CONCLUSION

This case describes a satellite lesion of endometrial tissue found in an unusual location, in a patient with no history, no risk factors, and no symptoms. The final diagnosis had been omitted from the differential—perhaps because the patient initially associated her symptoms with exercise and mentioned the correlation to her menstrual cycle as an afterthought. Fortunately, the correct diagnosis was made and the appropriate treatment provided.

There are numerous presentations of endometriosis; extrapelvic lesions can have very different, often vague, presentations when compared to the familiar symptoms of pelvic disease. Unfortunately, diagnosis is often delayed. Obscure presentations, in unusual sites, can further impede both speed and accuracy of diagnosis. To date, there are no lab tests or biomarkers to aid diagnosis; imaging studies are inconsistent. Until more accurate diagnostic tools become available, the diagnosis remains dependent on history taking, physical exam, and the clinical judgment of the provider. The astute clinician will recognize the catamenial pattern and consider endometriosis as part of the differential.

A 47-year-old woman was referred to the gynecology office by her primary care NP for surgical excision of an enlarging nodule on the right side of her mons pubis. Onset occurred about 6 months earlier. The patient reported that symptoms waxed and waned but had worsened progressively over the past 2 to 3 months, adding that the nodule hurt only occasionally. She noted that symptoms were exacerbated by exercise, specifically running. Further questioning prompted the observation that her symptoms were more noticeable at the time of menses.

The patient’s medical history was unremarkable, with no chronic conditions; her surgical history consisted of a wisdom tooth extraction. She had no known drug allergies. Her family history included cerebrovascular accident, hypertension, and arthritis. Reproductive history revealed that she was G1 P1, with a 38-week uncomplicated vaginal delivery. She experienced menarche at age 14, and her menses was regular at every 28 days. For the past 5 days, there had been no dysmenorrhea. The patient was married, exercised regularly, and did not use tobacco, alcohol, or illicit drugs.

On examination, the patient’s blood pressure was 123/73 mm Hg; heart rate, 77 beats/min; respiratory rate, 12 breaths/min; weight, 128 lb; height, 5 ft 7 in; O₂ saturation, 99% on room air; and BMI, 20. The patient was alert and oriented to person, place, and time. She was thin, appeared physically fit, and exhibited no signs of distress. Her physical exam was unremarkable, apart from a firm, minimally tender, well-circumscribed, 3.5 × 3.5–cm nodule right of midline on the mons pubis.

The patient was scheduled for outpatient surgical excision of a benign skin lesion (excluding skin tags) of the genitalia, 3.1 to 3.5 cm (CPT code 11424). During this procedure, it became evident that this was not a lipoma. The lesion was exceptionally hard, and it was difficult to discern if it was incorporated into the rectus abdominis near the point of attachment to the pubic symphysis. The lesion was unintentionally disrupted, revealing black powdery material within the capsule. The tissue was sent for a fast, frozen section that showed “soft tissue with extensive involvement by endometriosis.” The pathology report noted “[m]any endometrial glands in a background of stromal tissue. Necrosis was not a feature. No evidence of atypia.” The patient’s postoperative diagnosis was endometriosis.

DISCUSSION

Endometriosis occurs when endometrial or “endometrial-like” tissue is displaced to sites other than within the uterus. It is most frequently found on tissues close to the uterus, such as the ovaries or pelvic peritoneum. Estrogen is the driving force that feeds the endometrium, causing it to proliferate, whether inside or outside the uterus. Given this dependence on hormones, endometriosis occurs most often during a woman’s fertile years, although it can occur after menopause. Endometriosis is common, affecting at least 10% of premenopausal women; moreover, it is identified as the cause in 70% of all female chronic pelvic pain cases.^1-4

Endometriosis has certain identifiable features, such as chronic pain, dyspareunia, infertility, and menstrual and gastrointestinal symptoms. However, it is seldom diagnosed quickly; studies indicate that diagnosis can be delayed by 5 to 10 years after a patient has first sought treatment for symptoms.^2,4 Multiple factors contribute to a lag in diagnosis: Presentation is not always straightforward. There are no definitive lab values or biomarkers. Symptoms vary from patient to patient, as do clinical skills from one diagnostician to another.¹

Unlike pelvic endometriosis, inguinal endometriosis is not common; disease in this location encompasses only 0.3% to 0.6% of all diagnosed cases.^3,5-7 Since the discovery of the first known case of round ligament endometriosis in 1896, there have been only 70 cases reported in the medical literature.^6,7

If the more common form of endometriosis is frequently missed, this rarely seen variant presents an even greater diagnostic challenge. The typical presentation of inguinal endometriosis includes a firm nodule in the groin, accompanied by tenderness and swelling. A careful history will allude to pain that occurs cyclically with menses.

Cause

Among several theories about the etiology of endometriosis, the most popular has been retrograde menstruation.^1,4,5 According to this hypothesis, the flow of menstrual blood moves backward through the fallopian tubes, spilling into the pelvic cavity and carrying endometrial tissue with it. One theory purports that endometrial tissue is transplanted from the uterus to other areas of the body via the bloodstream or the lymphatics, much like a metastatic disease.^1,4 Another theory states that cells outside the uterus, which line the peritoneum, transform into endometrial cells through metaplasia.^4,5 Endometrial tissue can also be transplanted iatrogenically during surgery—for example, when endometrial tissue is displaced during a cesarean delivery, resulting in implants above the fascia and below the subcutaneous layers. Several other hypotheses concern stem-cell involvement, hormonal factors, immune system dysfunction, and genetics.^4,5 Currently, there are no definitive answers.

Location

During maturation, the parietal peritoneum develops a pouch called the processus vaginalis, which serves as a passageway for the gubernaculum to transport the round ligament running from the uterus, through the inguinal canal, and ending at the labia. After these structures reach their destination, in normal development, the processus vaginalis degenerates, closing the inguinal canal. Occasionally the processus vaginalis fails to close, allowing for a communication pathway between the peritoneal cavity and the inguinal canal. This leaves the canal vulnerable to the contents of the pelvic cavity, such as a hernia or hydrocele, and provides a clear path for endometriosis.^5-7 The implant found in the case patient was at the point where the external ring lies, just above the right pubic tubercle (see Figure 1).

Endometriosis implants can occur anywhere along the round ligament in either the intrapelvic or extrapelvic segments. Implants have also been found in the wall of a hernia sac, the wall of a Nuck canal hydrocele, or even in the subcutaneous tissue surrounding the inguinal canal.³ Interestingly, inguinal endometriosis occurs more often in the right side (up to 94% of cases) than in the left side, as was the case with our patient.^5-7 The reason for this predominance has not been established, although there are several theories, including one that suggests the left side is afforded protection by the sigmoid colon.^5-7

Laboratory diagnosis

Imaging, such as ultrasound and MRI, offers some diagnostic benefit, although its usefulness is most often realized in the pelvis. Pelvic ultrasound can be used to identify ovarian endometriomas.¹ MRI can help rule out, locate, or sometimes determine the degree of deep infiltrating endometriosis, which is an indispensable tool for surgical planning.^5,7 Unfortunately, the diagnostic accuracy for extra-pelvic lesions is variable; neither modality is particularly useful in identifying superficial lesions, which comprises most cases.

Ultrasound of the groin can be employed to evaluate for hernia; if a hernia has been excluded, histologic confirmation can be obtained via fine-needle aspiration of nodule contents.^5,7 One caveat is that these tests are helpful only if the clinician suspects the diagnosis and orders them. The definitive diagnostic test remains direct visualization, which requires laparoscopy.^1,5

Differential diagnosis

Lipoma was a favored diagnosis in this case because of the palpable, well-circumscribed borders, nontender on exam; intermittent, minimal tenderness; and no evidence of erythema or color change. A second possibility was an enlarged lymph node, which was less likely due to the location, large size, and sudden onset without any accompanying symptoms of infection or chronic illness. Finally, an inguinal hernia was least likely, again because of well-defined borders, no history of a lump in the area, a nodule that was not reducible, only minimal tenderness, and no color changes on the skin.

Management

Definitive treatment for inguinal endometriosis entails complete surgical excision.^5-7 The provider should be prepared to repair a defect after the excision; there is potential for a substantial defect that might require mesh. Additionally, a herniorrhaphy may be indicated if there is a coexisting hernia.⁵ The risk for recurrent disease in the inguinal canal after treatment is uncommon, unless the excision was not complete.³

There is an association between inguinal and pelvic endometriosis but not a direct correlation. Data on concomitant pelvic and inguinal endometriosis have been variable. In one case series of 9 patients diagnosed with inguinal endometriosis, none had a history of pelvic endometriosis, and only 1 was subsequently diagnosed with pelvic endometriosis.⁷ An increased association was noted for patients with implants found on the proximal segment of the round ligament.⁷ However, implants on the extrapelvic segment were not likely to represent pelvic disease but rather isolated lesions in the canal.⁷ For those with pelvic endometriosis, complications and recurrence are likely, resulting in the need for long-term treatment.

There is some debate in the literature whether to proceed with laparoscopy once inguinal endometriosis has been identified. Diagnostic laparoscopy to evaluate the pelvis is indicated for symptomatic patients or for cases in which an indirect inguinal hernia is suspected.⁵ Laparoscopy can offer the benefit of both a diagnostic tool and a mechanism for treatment. However, this is an invasive procedure that also incurs risks. The medical provider, in discussion with the patient, must weigh the risks against the benefits of an invasive procedure before determining how to proceed.

The lesion was excised completely. Since the patient had been entirely asymptomatic until age 47, and the risks of a potentially unnecessary surgery outweighed the theoretical benefits, the decision was made not to perform a diagnostic laparoscopy to investigate for pelvic endometriosis. The patient made a complete and uneventful recovery. No further treatment was initiated. She continues to be asymptomatic, denying any menstrual complaints, dyspareunia, or further problems with the groin.

CONCLUSION

This case describes a satellite lesion of endometrial tissue found in an unusual location, in a patient with no history, no risk factors, and no symptoms. The final diagnosis had been omitted from the differential—perhaps because the patient initially associated her symptoms with exercise and mentioned the correlation to her menstrual cycle as an afterthought. Fortunately, the correct diagnosis was made and the appropriate treatment provided.

There are numerous presentations of endometriosis; extrapelvic lesions can have very different, often vague, presentations when compared to the familiar symptoms of pelvic disease. Unfortunately, diagnosis is often delayed. Obscure presentations, in unusual sites, can further impede both speed and accuracy of diagnosis. To date, there are no lab tests or biomarkers to aid diagnosis; imaging studies are inconsistent. Until more accurate diagnostic tools become available, the diagnosis remains dependent on history taking, physical exam, and the clinical judgment of the provider. The astute clinician will recognize the catamenial pattern and consider endometriosis as part of the differential.

A 47-year-old woman was referred to the gynecology office by her primary care NP for surgical excision of an enlarging nodule on the right side of her mons pubis. Onset occurred about 6 months earlier. The patient reported that symptoms waxed and waned but had worsened progressively over the past 2 to 3 months, adding that the nodule hurt only occasionally. She noted that symptoms were exacerbated by exercise, specifically running. Further questioning prompted the observation that her symptoms were more noticeable at the time of menses.

The patient’s medical history was unremarkable, with no chronic conditions; her surgical history consisted of a wisdom tooth extraction. She had no known drug allergies. Her family history included cerebrovascular accident, hypertension, and arthritis. Reproductive history revealed that she was G1 P1, with a 38-week uncomplicated vaginal delivery. She experienced menarche at age 14, and her menses was regular at every 28 days. For the past 5 days, there had been no dysmenorrhea. The patient was married, exercised regularly, and did not use tobacco, alcohol, or illicit drugs.

On examination, the patient’s blood pressure was 123/73 mm Hg; heart rate, 77 beats/min; respiratory rate, 12 breaths/min; weight, 128 lb; height, 5 ft 7 in; O₂ saturation, 99% on room air; and BMI, 20. The patient was alert and oriented to person, place, and time. She was thin, appeared physically fit, and exhibited no signs of distress. Her physical exam was unremarkable, apart from a firm, minimally tender, well-circumscribed, 3.5 × 3.5–cm nodule right of midline on the mons pubis.

The patient was scheduled for outpatient surgical excision of a benign skin lesion (excluding skin tags) of the genitalia, 3.1 to 3.5 cm (CPT code 11424). During this procedure, it became evident that this was not a lipoma. The lesion was exceptionally hard, and it was difficult to discern if it was incorporated into the rectus abdominis near the point of attachment to the pubic symphysis. The lesion was unintentionally disrupted, revealing black powdery material within the capsule. The tissue was sent for a fast, frozen section that showed “soft tissue with extensive involvement by endometriosis.” The pathology report noted “[m]any endometrial glands in a background of stromal tissue. Necrosis was not a feature. No evidence of atypia.” The patient’s postoperative diagnosis was endometriosis.

DISCUSSION

Endometriosis occurs when endometrial or “endometrial-like” tissue is displaced to sites other than within the uterus. It is most frequently found on tissues close to the uterus, such as the ovaries or pelvic peritoneum. Estrogen is the driving force that feeds the endometrium, causing it to proliferate, whether inside or outside the uterus. Given this dependence on hormones, endometriosis occurs most often during a woman’s fertile years, although it can occur after menopause. Endometriosis is common, affecting at least 10% of premenopausal women; moreover, it is identified as the cause in 70% of all female chronic pelvic pain cases.^1-4

Endometriosis has certain identifiable features, such as chronic pain, dyspareunia, infertility, and menstrual and gastrointestinal symptoms. However, it is seldom diagnosed quickly; studies indicate that diagnosis can be delayed by 5 to 10 years after a patient has first sought treatment for symptoms.^2,4 Multiple factors contribute to a lag in diagnosis: Presentation is not always straightforward. There are no definitive lab values or biomarkers. Symptoms vary from patient to patient, as do clinical skills from one diagnostician to another.¹

Unlike pelvic endometriosis, inguinal endometriosis is not common; disease in this location encompasses only 0.3% to 0.6% of all diagnosed cases.^3,5-7 Since the discovery of the first known case of round ligament endometriosis in 1896, there have been only 70 cases reported in the medical literature.^6,7

If the more common form of endometriosis is frequently missed, this rarely seen variant presents an even greater diagnostic challenge. The typical presentation of inguinal endometriosis includes a firm nodule in the groin, accompanied by tenderness and swelling. A careful history will allude to pain that occurs cyclically with menses.

Cause

Among several theories about the etiology of endometriosis, the most popular has been retrograde menstruation.^1,4,5 According to this hypothesis, the flow of menstrual blood moves backward through the fallopian tubes, spilling into the pelvic cavity and carrying endometrial tissue with it. One theory purports that endometrial tissue is transplanted from the uterus to other areas of the body via the bloodstream or the lymphatics, much like a metastatic disease.^1,4 Another theory states that cells outside the uterus, which line the peritoneum, transform into endometrial cells through metaplasia.^4,5 Endometrial tissue can also be transplanted iatrogenically during surgery—for example, when endometrial tissue is displaced during a cesarean delivery, resulting in implants above the fascia and below the subcutaneous layers. Several other hypotheses concern stem-cell involvement, hormonal factors, immune system dysfunction, and genetics.^4,5 Currently, there are no definitive answers.

Location

During maturation, the parietal peritoneum develops a pouch called the processus vaginalis, which serves as a passageway for the gubernaculum to transport the round ligament running from the uterus, through the inguinal canal, and ending at the labia. After these structures reach their destination, in normal development, the processus vaginalis degenerates, closing the inguinal canal. Occasionally the processus vaginalis fails to close, allowing for a communication pathway between the peritoneal cavity and the inguinal canal. This leaves the canal vulnerable to the contents of the pelvic cavity, such as a hernia or hydrocele, and provides a clear path for endometriosis.^5-7 The implant found in the case patient was at the point where the external ring lies, just above the right pubic tubercle (see Figure 1).

Endometriosis implants can occur anywhere along the round ligament in either the intrapelvic or extrapelvic segments. Implants have also been found in the wall of a hernia sac, the wall of a Nuck canal hydrocele, or even in the subcutaneous tissue surrounding the inguinal canal.³ Interestingly, inguinal endometriosis occurs more often in the right side (up to 94% of cases) than in the left side, as was the case with our patient.^5-7 The reason for this predominance has not been established, although there are several theories, including one that suggests the left side is afforded protection by the sigmoid colon.^5-7

Laboratory diagnosis

Imaging, such as ultrasound and MRI, offers some diagnostic benefit, although its usefulness is most often realized in the pelvis. Pelvic ultrasound can be used to identify ovarian endometriomas.¹ MRI can help rule out, locate, or sometimes determine the degree of deep infiltrating endometriosis, which is an indispensable tool for surgical planning.^5,7 Unfortunately, the diagnostic accuracy for extra-pelvic lesions is variable; neither modality is particularly useful in identifying superficial lesions, which comprises most cases.

Ultrasound of the groin can be employed to evaluate for hernia; if a hernia has been excluded, histologic confirmation can be obtained via fine-needle aspiration of nodule contents.^5,7 One caveat is that these tests are helpful only if the clinician suspects the diagnosis and orders them. The definitive diagnostic test remains direct visualization, which requires laparoscopy.^1,5

Differential diagnosis

Lipoma was a favored diagnosis in this case because of the palpable, well-circumscribed borders, nontender on exam; intermittent, minimal tenderness; and no evidence of erythema or color change. A second possibility was an enlarged lymph node, which was less likely due to the location, large size, and sudden onset without any accompanying symptoms of infection or chronic illness. Finally, an inguinal hernia was least likely, again because of well-defined borders, no history of a lump in the area, a nodule that was not reducible, only minimal tenderness, and no color changes on the skin.

Management

Definitive treatment for inguinal endometriosis entails complete surgical excision.^5-7 The provider should be prepared to repair a defect after the excision; there is potential for a substantial defect that might require mesh. Additionally, a herniorrhaphy may be indicated if there is a coexisting hernia.⁵ The risk for recurrent disease in the inguinal canal after treatment is uncommon, unless the excision was not complete.³

There is an association between inguinal and pelvic endometriosis but not a direct correlation. Data on concomitant pelvic and inguinal endometriosis have been variable. In one case series of 9 patients diagnosed with inguinal endometriosis, none had a history of pelvic endometriosis, and only 1 was subsequently diagnosed with pelvic endometriosis.⁷ An increased association was noted for patients with implants found on the proximal segment of the round ligament.⁷ However, implants on the extrapelvic segment were not likely to represent pelvic disease but rather isolated lesions in the canal.⁷ For those with pelvic endometriosis, complications and recurrence are likely, resulting in the need for long-term treatment.

There is some debate in the literature whether to proceed with laparoscopy once inguinal endometriosis has been identified. Diagnostic laparoscopy to evaluate the pelvis is indicated for symptomatic patients or for cases in which an indirect inguinal hernia is suspected.⁵ Laparoscopy can offer the benefit of both a diagnostic tool and a mechanism for treatment. However, this is an invasive procedure that also incurs risks. The medical provider, in discussion with the patient, must weigh the risks against the benefits of an invasive procedure before determining how to proceed.

The lesion was excised completely. Since the patient had been entirely asymptomatic until age 47, and the risks of a potentially unnecessary surgery outweighed the theoretical benefits, the decision was made not to perform a diagnostic laparoscopy to investigate for pelvic endometriosis. The patient made a complete and uneventful recovery. No further treatment was initiated. She continues to be asymptomatic, denying any menstrual complaints, dyspareunia, or further problems with the groin.

CONCLUSION

This case describes a satellite lesion of endometrial tissue found in an unusual location, in a patient with no history, no risk factors, and no symptoms. The final diagnosis had been omitted from the differential—perhaps because the patient initially associated her symptoms with exercise and mentioned the correlation to her menstrual cycle as an afterthought. Fortunately, the correct diagnosis was made and the appropriate treatment provided.

There are numerous presentations of endometriosis; extrapelvic lesions can have very different, often vague, presentations when compared to the familiar symptoms of pelvic disease. Unfortunately, diagnosis is often delayed. Obscure presentations, in unusual sites, can further impede both speed and accuracy of diagnosis. To date, there are no lab tests or biomarkers to aid diagnosis; imaging studies are inconsistent. Until more accurate diagnostic tools become available, the diagnosis remains dependent on history taking, physical exam, and the clinical judgment of the provider. The astute clinician will recognize the catamenial pattern and consider endometriosis as part of the differential.

A new study has found that distributing HIV self-tests to at-risk groups such as men who have sex with men can increase testing frequency and uncover more previously undiagnosed infections.

“Based on these findings, HIV prevention programs might consider adding an HIV self-testing mail distribution component to their portfolio of HIV prevention services for high-risk populations,” wrote Robin J. MacGowan, MPH, of the Centers for Disease Control and Prevention and coauthors. The study was published in JAMA Internal Medicine.

To assess the potential benefits of expanded HIV self-testing, the CDC sponsored a 12-month randomized clinical trial called the Evaluation of Rapid HIV Self-testing Among MSM Project (eSTAMP). Participants were recruited via social media, music and dating websites; criteria included being aged at least 18 years, never having tested positive for HIV, and having engaged in anal sex with at least one man in the past year. The 2,665 participants were assigned to either the self-testing (ST) group (n = 1,325) or the control group (n = 1,340); the ST group received four self-tests in the mail with the option for more each quarter. All participants were asked to complete follow-up surveys every 3 months.

Of all participants, 1,991 (74.7%) initiated at least one follow-up survey. Participants in the ST group reported testing more frequently than those in the control group (an average of 5.3 tests vs. 1.5 tests; P less than .001). In addition, a much higher percentage of ST participants tested at least three times in 12 months (777 of 1014 [76.6%]), compared with controls (215 of 977 [22.0%]). A total of 36 participants tested newly positive for HIV during the study; over the first 3 months, 12 of the 14 infections were identified in the ST group (P less than .007). Over 12 months, 25 of the infections came from the ST group, compared with 11 in the control group (P = .02).

When HIV tests are free and convenient, members of high-risk populations will use them, wrote Julia M. Janssen, MD, of the University of California, San Francisco, and Mitchell H. Katz, MD, of New York City Health and Hospitals in an accompanying editorial (JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5442). But tests are not enough; the authors noted the role of primary care physicians in prescribing pre-exposure prophylaxis (PrEP) for at-risk patients as key in decreasing rates of new HIV diagnoses.

“The self-testing kits targeting individuals at high risk of acquiring HIV complement the use of PrEP,” they added, “and are another way to accelerate the end of the epidemic.”

The study was funded by the CDC. One author reported receiving grants and fees from the CDC and the National Institutes of Health, along with personal fees from Elsevier and the Ontario HIV Treatment Network. Dr. Katz reported receiving royalties for a chapter on HIV in Lange’s Current Medicine and Diagnostic Testing.

SOURCE: MacGowan RJ et al. JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5222.

A new study has found that distributing HIV self-tests to at-risk groups such as men who have sex with men can increase testing frequency and uncover more previously undiagnosed infections.

“Based on these findings, HIV prevention programs might consider adding an HIV self-testing mail distribution component to their portfolio of HIV prevention services for high-risk populations,” wrote Robin J. MacGowan, MPH, of the Centers for Disease Control and Prevention and coauthors. The study was published in JAMA Internal Medicine.

To assess the potential benefits of expanded HIV self-testing, the CDC sponsored a 12-month randomized clinical trial called the Evaluation of Rapid HIV Self-testing Among MSM Project (eSTAMP). Participants were recruited via social media, music and dating websites; criteria included being aged at least 18 years, never having tested positive for HIV, and having engaged in anal sex with at least one man in the past year. The 2,665 participants were assigned to either the self-testing (ST) group (n = 1,325) or the control group (n = 1,340); the ST group received four self-tests in the mail with the option for more each quarter. All participants were asked to complete follow-up surveys every 3 months.

Of all participants, 1,991 (74.7%) initiated at least one follow-up survey. Participants in the ST group reported testing more frequently than those in the control group (an average of 5.3 tests vs. 1.5 tests; P less than .001). In addition, a much higher percentage of ST participants tested at least three times in 12 months (777 of 1014 [76.6%]), compared with controls (215 of 977 [22.0%]). A total of 36 participants tested newly positive for HIV during the study; over the first 3 months, 12 of the 14 infections were identified in the ST group (P less than .007). Over 12 months, 25 of the infections came from the ST group, compared with 11 in the control group (P = .02).

When HIV tests are free and convenient, members of high-risk populations will use them, wrote Julia M. Janssen, MD, of the University of California, San Francisco, and Mitchell H. Katz, MD, of New York City Health and Hospitals in an accompanying editorial (JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5442). But tests are not enough; the authors noted the role of primary care physicians in prescribing pre-exposure prophylaxis (PrEP) for at-risk patients as key in decreasing rates of new HIV diagnoses.

“The self-testing kits targeting individuals at high risk of acquiring HIV complement the use of PrEP,” they added, “and are another way to accelerate the end of the epidemic.”

The study was funded by the CDC. One author reported receiving grants and fees from the CDC and the National Institutes of Health, along with personal fees from Elsevier and the Ontario HIV Treatment Network. Dr. Katz reported receiving royalties for a chapter on HIV in Lange’s Current Medicine and Diagnostic Testing.

SOURCE: MacGowan RJ et al. JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5222.

A new study has found that distributing HIV self-tests to at-risk groups such as men who have sex with men can increase testing frequency and uncover more previously undiagnosed infections.

“Based on these findings, HIV prevention programs might consider adding an HIV self-testing mail distribution component to their portfolio of HIV prevention services for high-risk populations,” wrote Robin J. MacGowan, MPH, of the Centers for Disease Control and Prevention and coauthors. The study was published in JAMA Internal Medicine.

To assess the potential benefits of expanded HIV self-testing, the CDC sponsored a 12-month randomized clinical trial called the Evaluation of Rapid HIV Self-testing Among MSM Project (eSTAMP). Participants were recruited via social media, music and dating websites; criteria included being aged at least 18 years, never having tested positive for HIV, and having engaged in anal sex with at least one man in the past year. The 2,665 participants were assigned to either the self-testing (ST) group (n = 1,325) or the control group (n = 1,340); the ST group received four self-tests in the mail with the option for more each quarter. All participants were asked to complete follow-up surveys every 3 months.

Of all participants, 1,991 (74.7%) initiated at least one follow-up survey. Participants in the ST group reported testing more frequently than those in the control group (an average of 5.3 tests vs. 1.5 tests; P less than .001). In addition, a much higher percentage of ST participants tested at least three times in 12 months (777 of 1014 [76.6%]), compared with controls (215 of 977 [22.0%]). A total of 36 participants tested newly positive for HIV during the study; over the first 3 months, 12 of the 14 infections were identified in the ST group (P less than .007). Over 12 months, 25 of the infections came from the ST group, compared with 11 in the control group (P = .02).

When HIV tests are free and convenient, members of high-risk populations will use them, wrote Julia M. Janssen, MD, of the University of California, San Francisco, and Mitchell H. Katz, MD, of New York City Health and Hospitals in an accompanying editorial (JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5442). But tests are not enough; the authors noted the role of primary care physicians in prescribing pre-exposure prophylaxis (PrEP) for at-risk patients as key in decreasing rates of new HIV diagnoses.

“The self-testing kits targeting individuals at high risk of acquiring HIV complement the use of PrEP,” they added, “and are another way to accelerate the end of the epidemic.”

The study was funded by the CDC. One author reported receiving grants and fees from the CDC and the National Institutes of Health, along with personal fees from Elsevier and the Ontario HIV Treatment Network. Dr. Katz reported receiving royalties for a chapter on HIV in Lange’s Current Medicine and Diagnostic Testing.

SOURCE: MacGowan RJ et al. JAMA Intern Med. 2019 Nov 18. doi: 10.1001/jamainternmed.2019.5222.

SAN FRANCISCO – Opioid prescription is surprisingly high after laparoscopic colorectal surgery, and is higher at larger hospitals and in some regions of the United States, according to a new study.

“In theory, for management of pain, any opioids required should be lower after laparoscopic surgery, but opioids are still ubiquitous and prescribing patterns have largely been unchanged with laparoscopy,” Deborah S. Keller, MD, assistant professor of surgery at Columbia University, New York, said at the annual clinical congress of the American College of Surgeons.

Several studies show wide variation in opioid use and prescribing after laparoscopic colorectal surgery, Dr. Keller said. She also pointed out that available data are limited on inpatient opioid use and the causes of high opioid use.

The team analyzed records of 18,395 subjects from the Premier Inpatient Database, between Jan. 1, 2014, and Sept. 30, 2015. The mean age was 61 years, and 54% were female. The distribution of hospital-stay milligram morphine equivalents (MME) was 48 at the 25th percentile, 108 at the 50th, and 246 at the 75th percentile. Overall, 18% of patients were in the high use category.

Some factors were associated with high opioid use, including emergency surgery (odds ratio, 1.28; P = .0002), being aged 18-34 (OR, 5.8; P less than .0001), major severity of illness (OR, 4.2; P less than .0001), chronic obstructive pulmonary disease comorbidity (OR, 1.13; P =.0350), having Medicaid insurance (OR, 1.35; P less than .0001), and being treated in a rural hospital (OR, 1.44; P less than.0001).

Factors associated with lower opioid use included female sex (OR, 0.90; P = .0064), being treated in a facility with fewer than 500 beds (OR, 0.706-0.822, all statistically significant), being treated in the Midwest (OR, 0.62; P less than .0001) or the South (OR, 0.66; P less than .0001), and treatment by a surgeon with a lower surgical volume (fewer than 65 cases vs. 300; OR, 0.58; P = .0286).

The study was limited by its reliance on administrative data, and one questioner at the session wondered about the validity of the 75% cutoff for high use, suggesting that it would be better to pick a value that was associated with a known increased risk of opioid dependence.

The findings could help inform future guidelines, Dr. Keller said. “On a local level, it can help optimize enhanced recovery protocols, (assist) providers to proactively recognize patients and scenarios at risk for high use, and create targeted education for younger patients, hospitals in specific geographic regions, and larger bedside hospitals so that they can follow best practices,” she added.

The finding that institutions with fewer beds were associated with lower chances of high opioid use was a surprise. “We’re looking into that,” she said.

Dr. Keller had no relevant financial disclosures.

SOURCE: Keller DS et al. Clinical Congress 2019, Abstract.

SAN FRANCISCO – Opioid prescription is surprisingly high after laparoscopic colorectal surgery, and is higher at larger hospitals and in some regions of the United States, according to a new study.

“In theory, for management of pain, any opioids required should be lower after laparoscopic surgery, but opioids are still ubiquitous and prescribing patterns have largely been unchanged with laparoscopy,” Deborah S. Keller, MD, assistant professor of surgery at Columbia University, New York, said at the annual clinical congress of the American College of Surgeons.

Several studies show wide variation in opioid use and prescribing after laparoscopic colorectal surgery, Dr. Keller said. She also pointed out that available data are limited on inpatient opioid use and the causes of high opioid use.

The team analyzed records of 18,395 subjects from the Premier Inpatient Database, between Jan. 1, 2014, and Sept. 30, 2015. The mean age was 61 years, and 54% were female. The distribution of hospital-stay milligram morphine equivalents (MME) was 48 at the 25th percentile, 108 at the 50th, and 246 at the 75th percentile. Overall, 18% of patients were in the high use category.

Some factors were associated with high opioid use, including emergency surgery (odds ratio, 1.28; P = .0002), being aged 18-34 (OR, 5.8; P less than .0001), major severity of illness (OR, 4.2; P less than .0001), chronic obstructive pulmonary disease comorbidity (OR, 1.13; P =.0350), having Medicaid insurance (OR, 1.35; P less than .0001), and being treated in a rural hospital (OR, 1.44; P less than.0001).

Factors associated with lower opioid use included female sex (OR, 0.90; P = .0064), being treated in a facility with fewer than 500 beds (OR, 0.706-0.822, all statistically significant), being treated in the Midwest (OR, 0.62; P less than .0001) or the South (OR, 0.66; P less than .0001), and treatment by a surgeon with a lower surgical volume (fewer than 65 cases vs. 300; OR, 0.58; P = .0286).

The study was limited by its reliance on administrative data, and one questioner at the session wondered about the validity of the 75% cutoff for high use, suggesting that it would be better to pick a value that was associated with a known increased risk of opioid dependence.

The findings could help inform future guidelines, Dr. Keller said. “On a local level, it can help optimize enhanced recovery protocols, (assist) providers to proactively recognize patients and scenarios at risk for high use, and create targeted education for younger patients, hospitals in specific geographic regions, and larger bedside hospitals so that they can follow best practices,” she added.

The finding that institutions with fewer beds were associated with lower chances of high opioid use was a surprise. “We’re looking into that,” she said.

Dr. Keller had no relevant financial disclosures.

SOURCE: Keller DS et al. Clinical Congress 2019, Abstract.

SAN FRANCISCO – Opioid prescription is surprisingly high after laparoscopic colorectal surgery, and is higher at larger hospitals and in some regions of the United States, according to a new study.

“In theory, for management of pain, any opioids required should be lower after laparoscopic surgery, but opioids are still ubiquitous and prescribing patterns have largely been unchanged with laparoscopy,” Deborah S. Keller, MD, assistant professor of surgery at Columbia University, New York, said at the annual clinical congress of the American College of Surgeons.

Several studies show wide variation in opioid use and prescribing after laparoscopic colorectal surgery, Dr. Keller said. She also pointed out that available data are limited on inpatient opioid use and the causes of high opioid use.

The team analyzed records of 18,395 subjects from the Premier Inpatient Database, between Jan. 1, 2014, and Sept. 30, 2015. The mean age was 61 years, and 54% were female. The distribution of hospital-stay milligram morphine equivalents (MME) was 48 at the 25th percentile, 108 at the 50th, and 246 at the 75th percentile. Overall, 18% of patients were in the high use category.

Some factors were associated with high opioid use, including emergency surgery (odds ratio, 1.28; P = .0002), being aged 18-34 (OR, 5.8; P less than .0001), major severity of illness (OR, 4.2; P less than .0001), chronic obstructive pulmonary disease comorbidity (OR, 1.13; P =.0350), having Medicaid insurance (OR, 1.35; P less than .0001), and being treated in a rural hospital (OR, 1.44; P less than.0001).

Factors associated with lower opioid use included female sex (OR, 0.90; P = .0064), being treated in a facility with fewer than 500 beds (OR, 0.706-0.822, all statistically significant), being treated in the Midwest (OR, 0.62; P less than .0001) or the South (OR, 0.66; P less than .0001), and treatment by a surgeon with a lower surgical volume (fewer than 65 cases vs. 300; OR, 0.58; P = .0286).

The study was limited by its reliance on administrative data, and one questioner at the session wondered about the validity of the 75% cutoff for high use, suggesting that it would be better to pick a value that was associated with a known increased risk of opioid dependence.

The findings could help inform future guidelines, Dr. Keller said. “On a local level, it can help optimize enhanced recovery protocols, (assist) providers to proactively recognize patients and scenarios at risk for high use, and create targeted education for younger patients, hospitals in specific geographic regions, and larger bedside hospitals so that they can follow best practices,” she added.

The finding that institutions with fewer beds were associated with lower chances of high opioid use was a surprise. “We’re looking into that,” she said.

Dr. Keller had no relevant financial disclosures.

SOURCE: Keller DS et al. Clinical Congress 2019, Abstract.

LAS VEGAS – The patient, a 61-year-old man, came to see a dermatologist here about subcutaneous masses on his left arm, abdomen, and on both thighs.

It didn’t take long for Curt Samlaska, MD, of the University of Nevada, Reno, to link the masses to the patient’s daily regimen of seven insulin injections.

But diagnosing the condition required more than asking a few questions. At first, the man appeared to suffer from lipohypertrophy – a lump caused by an accumulation of fat at the site of insulin injections. But, Dr. Samlaska told colleagues, the patient had a different condition that’s barely been discussed in the dermatologic literature – insulin-derived amyloidosis, also known as “insulin ball.”

“It’s probably much more prevalent than we currently appreciate,” said Dr. Samlaska, who spoke in a presentation at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Many cases are not [fully] evaluated and thought to be lipohypertrophy.”

Dr. Samlaska’s patient had suffered from diabetes since age 23 and tightly controls his blood sugar through seven daily injections. He injects short-acting insulin into his arms and abdomen, and long-acting insulin into his thighs.

The masses began appearing about 10 years ago, he told Dr. Samlaska, and he’s suffered more pain while injecting them over time. But the masses are easier to grasp during injections, and the patient’s body did not offer many other sites for injections.

According to Dr. Samlaska, there are about 75 case reports of insulin ball in the medical literature, almost all in endocrinology journals. Ninety percent have a single lump, most commonly in the abdomen, and most have poor glycemic control, he said. (His patient is an outlier.)

Research suggests that insulin balls absorb about 34% of the insulin that’s injected, meaning that patients must inject more than usual to get the same effect. Be careful to advise patients about this, Dr. Samlaska said, because they might try alternative injection sites and get a sudden unexpected flood of insulin – potentially causing hypoglycemia.

He added that another drug – the HIV fusion inhibitor enfuvirtide – also has been linked to amyloidosis.

Pathology can offer insight into whether a mass is an insulin ball or a case of lipohypertrophy, he said. “They’re difficult to distinguish on clinical grounds,” he said, although lipohypertrophy masses are firmer, and they shrink when patients stop injecting insulin. Insulin balls do not.

The treatment for insulin balls is surgical excision, he said. “It’s very easy to do. With the extrusion technique, it comes out like a cheese, like a cyst.”

He said his patient was scheduled to soon undergo excision treatment.

Dr. Samlaska reported no relevant disclosures. SDEF and this news organization are owned by the same parent company.

LAS VEGAS – The patient, a 61-year-old man, came to see a dermatologist here about subcutaneous masses on his left arm, abdomen, and on both thighs.

It didn’t take long for Curt Samlaska, MD, of the University of Nevada, Reno, to link the masses to the patient’s daily regimen of seven insulin injections.

But diagnosing the condition required more than asking a few questions. At first, the man appeared to suffer from lipohypertrophy – a lump caused by an accumulation of fat at the site of insulin injections. But, Dr. Samlaska told colleagues, the patient had a different condition that’s barely been discussed in the dermatologic literature – insulin-derived amyloidosis, also known as “insulin ball.”

“It’s probably much more prevalent than we currently appreciate,” said Dr. Samlaska, who spoke in a presentation at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Many cases are not [fully] evaluated and thought to be lipohypertrophy.”

Dr. Samlaska’s patient had suffered from diabetes since age 23 and tightly controls his blood sugar through seven daily injections. He injects short-acting insulin into his arms and abdomen, and long-acting insulin into his thighs.

The masses began appearing about 10 years ago, he told Dr. Samlaska, and he’s suffered more pain while injecting them over time. But the masses are easier to grasp during injections, and the patient’s body did not offer many other sites for injections.

According to Dr. Samlaska, there are about 75 case reports of insulin ball in the medical literature, almost all in endocrinology journals. Ninety percent have a single lump, most commonly in the abdomen, and most have poor glycemic control, he said. (His patient is an outlier.)

Research suggests that insulin balls absorb about 34% of the insulin that’s injected, meaning that patients must inject more than usual to get the same effect. Be careful to advise patients about this, Dr. Samlaska said, because they might try alternative injection sites and get a sudden unexpected flood of insulin – potentially causing hypoglycemia.

He added that another drug – the HIV fusion inhibitor enfuvirtide – also has been linked to amyloidosis.

Pathology can offer insight into whether a mass is an insulin ball or a case of lipohypertrophy, he said. “They’re difficult to distinguish on clinical grounds,” he said, although lipohypertrophy masses are firmer, and they shrink when patients stop injecting insulin. Insulin balls do not.

The treatment for insulin balls is surgical excision, he said. “It’s very easy to do. With the extrusion technique, it comes out like a cheese, like a cyst.”

He said his patient was scheduled to soon undergo excision treatment.

Dr. Samlaska reported no relevant disclosures. SDEF and this news organization are owned by the same parent company.

LAS VEGAS – The patient, a 61-year-old man, came to see a dermatologist here about subcutaneous masses on his left arm, abdomen, and on both thighs.

It didn’t take long for Curt Samlaska, MD, of the University of Nevada, Reno, to link the masses to the patient’s daily regimen of seven insulin injections.

But diagnosing the condition required more than asking a few questions. At first, the man appeared to suffer from lipohypertrophy – a lump caused by an accumulation of fat at the site of insulin injections. But, Dr. Samlaska told colleagues, the patient had a different condition that’s barely been discussed in the dermatologic literature – insulin-derived amyloidosis, also known as “insulin ball.”

“It’s probably much more prevalent than we currently appreciate,” said Dr. Samlaska, who spoke in a presentation at the Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “Many cases are not [fully] evaluated and thought to be lipohypertrophy.”

Dr. Samlaska’s patient had suffered from diabetes since age 23 and tightly controls his blood sugar through seven daily injections. He injects short-acting insulin into his arms and abdomen, and long-acting insulin into his thighs.

The masses began appearing about 10 years ago, he told Dr. Samlaska, and he’s suffered more pain while injecting them over time. But the masses are easier to grasp during injections, and the patient’s body did not offer many other sites for injections.

According to Dr. Samlaska, there are about 75 case reports of insulin ball in the medical literature, almost all in endocrinology journals. Ninety percent have a single lump, most commonly in the abdomen, and most have poor glycemic control, he said. (His patient is an outlier.)

Research suggests that insulin balls absorb about 34% of the insulin that’s injected, meaning that patients must inject more than usual to get the same effect. Be careful to advise patients about this, Dr. Samlaska said, because they might try alternative injection sites and get a sudden unexpected flood of insulin – potentially causing hypoglycemia.

He added that another drug – the HIV fusion inhibitor enfuvirtide – also has been linked to amyloidosis.

Pathology can offer insight into whether a mass is an insulin ball or a case of lipohypertrophy, he said. “They’re difficult to distinguish on clinical grounds,” he said, although lipohypertrophy masses are firmer, and they shrink when patients stop injecting insulin. Insulin balls do not.

The treatment for insulin balls is surgical excision, he said. “It’s very easy to do. With the extrusion technique, it comes out like a cheese, like a cyst.”

He said his patient was scheduled to soon undergo excision treatment.

Dr. Samlaska reported no relevant disclosures. SDEF and this news organization are owned by the same parent company.

Adolescence is a critical period of development that brings with it unique health challenges, which has prompted the American Academy of Pediatrics to publish a policy statement addressing those issues.

“The importance of addressing the physical and mental health of adolescents has become more evident, with investigators in recent studies pointing to the fact that unmet health needs during adolescence and in the transition to adulthood predict not only poor health outcomes as adults but also lower quality of life in adulthood,” wrote lead authors Elizabeth M. Alderman, MD, and Cora Collette Breuner, MD, MPH, of the AAP’s Committee on Adolescence.

Lisa Quarfoth/Thinkstock

The first key health risk the authors highlighted was risky and risk-taking behaviors, pointing out that nearly three-quarters of adolescent deaths result from vehicle crashes, injuries from firearms, alcohol and illicit substances, homicide, or suicide. They also cited increased concern about the use of e-cigarettes among adolescents.

Recommendations exist on screening for and counseling on high-risk behaviors, but evidence showing that relatively few adolescents actually receive any kind of preventive counseling or discuss these health risks with pediatricians or primary care physicians suggests that improvement is needed.

“New screening codes for depression, substance use, and alcohol and tobacco use as well as brief intervention services may provide opportunities to receive payment for the services pediatricians are providing to adolescents,” wrote Dr. Alderman of the division of adolescent medicine in the department of pediatrics at Albert Einstein College of Medicine and the Children’s Hospital at Montefiore, New York, and Dr. Breuner of the division of adolescent medicine at the University of Washington and Seattle Children’s Hospital.

Thanks to technological advances in pediatric medical care, more adolescents are being identified with chronic medical conditions and developmental challenges. One survey suggested that as many as 31% of adolescents have one moderate to severe chronic health condition, such as asthma, cardiac disease, HIV, and developmental disabilities. Many, however, have unmet health needs that could affect their physical growth and development during adolescence.

The paper also raised the importance of providing culturally competent health care approaches and support for minority youth, with evidence suggesting this group of adolescents is at risk of depression because of the isolation and discrimination they experience.

Similarly, the statement acknowledged the growing diversity of adolescent populations – for example, adolescents who identify as lesbian, gay, bisexual, or transgender – and the importance of delivering appropriate care to those populations.

“Sexual orientation and behaviors should be assessed by the pediatrician without making assumptions,” the authors wrote. “Adolescents should be allowed to apply and explain the labels they choose to use for sexuality and gender using open-ended questions.”

The authors drew attention to the greater mental health risks of adolescents, pointing out that about one in five adolescents have a diagnosable mental health disorder and one-quarter of adults with mood disorders had their first major depressive episode during adolescence. They also cited the Centers for Disease Control and Prevention’s 2017 Youth Risk Behavior Survey of high school students, which showed that adolescents with a parent serving in the military are at increased risk of suicidal ideation.

In addition, Dr. Alderman and Dr. Breuner said, mental health problems experienced by adolescents often are comorbid with eating disorders. Formerly obese adolescents, male teenagers, and young people from lower socioeconomic groups are increasingly developing anorexia nervosa, bulimia nervosa, and other disordered eating.

The paper called for more financial, educational, and training support for pediatricians and other health care professionals to enable them to better meet the health and developmental needs of adolescents.

Dr. Alderman and Dr. Breuner declared having no conflicts of interest.

SOURCE: Alderman EM and Breuner CC. Pediatrics. 2019 Nov 18. doi: 10.1542/peds.2019-3150 .

Adolescence is a critical period of development that brings with it unique health challenges, which has prompted the American Academy of Pediatrics to publish a policy statement addressing those issues.

“The importance of addressing the physical and mental health of adolescents has become more evident, with investigators in recent studies pointing to the fact that unmet health needs during adolescence and in the transition to adulthood predict not only poor health outcomes as adults but also lower quality of life in adulthood,” wrote lead authors Elizabeth M. Alderman, MD, and Cora Collette Breuner, MD, MPH, of the AAP’s Committee on Adolescence.

Lisa Quarfoth/Thinkstock

The first key health risk the authors highlighted was risky and risk-taking behaviors, pointing out that nearly three-quarters of adolescent deaths result from vehicle crashes, injuries from firearms, alcohol and illicit substances, homicide, or suicide. They also cited increased concern about the use of e-cigarettes among adolescents.

Recommendations exist on screening for and counseling on high-risk behaviors, but evidence showing that relatively few adolescents actually receive any kind of preventive counseling or discuss these health risks with pediatricians or primary care physicians suggests that improvement is needed.

“New screening codes for depression, substance use, and alcohol and tobacco use as well as brief intervention services may provide opportunities to receive payment for the services pediatricians are providing to adolescents,” wrote Dr. Alderman of the division of adolescent medicine in the department of pediatrics at Albert Einstein College of Medicine and the Children’s Hospital at Montefiore, New York, and Dr. Breuner of the division of adolescent medicine at the University of Washington and Seattle Children’s Hospital.

Thanks to technological advances in pediatric medical care, more adolescents are being identified with chronic medical conditions and developmental challenges. One survey suggested that as many as 31% of adolescents have one moderate to severe chronic health condition, such as asthma, cardiac disease, HIV, and developmental disabilities. Many, however, have unmet health needs that could affect their physical growth and development during adolescence.

The paper also raised the importance of providing culturally competent health care approaches and support for minority youth, with evidence suggesting this group of adolescents is at risk of depression because of the isolation and discrimination they experience.

Similarly, the statement acknowledged the growing diversity of adolescent populations – for example, adolescents who identify as lesbian, gay, bisexual, or transgender – and the importance of delivering appropriate care to those populations.

“Sexual orientation and behaviors should be assessed by the pediatrician without making assumptions,” the authors wrote. “Adolescents should be allowed to apply and explain the labels they choose to use for sexuality and gender using open-ended questions.”

The authors drew attention to the greater mental health risks of adolescents, pointing out that about one in five adolescents have a diagnosable mental health disorder and one-quarter of adults with mood disorders had their first major depressive episode during adolescence. They also cited the Centers for Disease Control and Prevention’s 2017 Youth Risk Behavior Survey of high school students, which showed that adolescents with a parent serving in the military are at increased risk of suicidal ideation.

In addition, Dr. Alderman and Dr. Breuner said, mental health problems experienced by adolescents often are comorbid with eating disorders. Formerly obese adolescents, male teenagers, and young people from lower socioeconomic groups are increasingly developing anorexia nervosa, bulimia nervosa, and other disordered eating.

The paper called for more financial, educational, and training support for pediatricians and other health care professionals to enable them to better meet the health and developmental needs of adolescents.

Dr. Alderman and Dr. Breuner declared having no conflicts of interest.

SOURCE: Alderman EM and Breuner CC. Pediatrics. 2019 Nov 18. doi: 10.1542/peds.2019-3150 .

Adolescence is a critical period of development that brings with it unique health challenges, which has prompted the American Academy of Pediatrics to publish a policy statement addressing those issues.

“The importance of addressing the physical and mental health of adolescents has become more evident, with investigators in recent studies pointing to the fact that unmet health needs during adolescence and in the transition to adulthood predict not only poor health outcomes as adults but also lower quality of life in adulthood,” wrote lead authors Elizabeth M. Alderman, MD, and Cora Collette Breuner, MD, MPH, of the AAP’s Committee on Adolescence.

Lisa Quarfoth/Thinkstock

The first key health risk the authors highlighted was risky and risk-taking behaviors, pointing out that nearly three-quarters of adolescent deaths result from vehicle crashes, injuries from firearms, alcohol and illicit substances, homicide, or suicide. They also cited increased concern about the use of e-cigarettes among adolescents.

Recommendations exist on screening for and counseling on high-risk behaviors, but evidence showing that relatively few adolescents actually receive any kind of preventive counseling or discuss these health risks with pediatricians or primary care physicians suggests that improvement is needed.

“New screening codes for depression, substance use, and alcohol and tobacco use as well as brief intervention services may provide opportunities to receive payment for the services pediatricians are providing to adolescents,” wrote Dr. Alderman of the division of adolescent medicine in the department of pediatrics at Albert Einstein College of Medicine and the Children’s Hospital at Montefiore, New York, and Dr. Breuner of the division of adolescent medicine at the University of Washington and Seattle Children’s Hospital.

Thanks to technological advances in pediatric medical care, more adolescents are being identified with chronic medical conditions and developmental challenges. One survey suggested that as many as 31% of adolescents have one moderate to severe chronic health condition, such as asthma, cardiac disease, HIV, and developmental disabilities. Many, however, have unmet health needs that could affect their physical growth and development during adolescence.

The paper also raised the importance of providing culturally competent health care approaches and support for minority youth, with evidence suggesting this group of adolescents is at risk of depression because of the isolation and discrimination they experience.

Similarly, the statement acknowledged the growing diversity of adolescent populations – for example, adolescents who identify as lesbian, gay, bisexual, or transgender – and the importance of delivering appropriate care to those populations.

“Sexual orientation and behaviors should be assessed by the pediatrician without making assumptions,” the authors wrote. “Adolescents should be allowed to apply and explain the labels they choose to use for sexuality and gender using open-ended questions.”

The authors drew attention to the greater mental health risks of adolescents, pointing out that about one in five adolescents have a diagnosable mental health disorder and one-quarter of adults with mood disorders had their first major depressive episode during adolescence. They also cited the Centers for Disease Control and Prevention’s 2017 Youth Risk Behavior Survey of high school students, which showed that adolescents with a parent serving in the military are at increased risk of suicidal ideation.

In addition, Dr. Alderman and Dr. Breuner said, mental health problems experienced by adolescents often are comorbid with eating disorders. Formerly obese adolescents, male teenagers, and young people from lower socioeconomic groups are increasingly developing anorexia nervosa, bulimia nervosa, and other disordered eating.

The paper called for more financial, educational, and training support for pediatricians and other health care professionals to enable them to better meet the health and developmental needs of adolescents.

Dr. Alderman and Dr. Breuner declared having no conflicts of interest.

SOURCE: Alderman EM and Breuner CC. Pediatrics. 2019 Nov 18. doi: 10.1542/peds.2019-3150 .